Review pubs.acs.org/CR
Alkaloids and Isoprenoids Modification by Copper(I)-Catalyzed Huisgen 1,3-Dipolar Cycloaddition (Click Chemistry): Toward New Functions and Molecular Architectures Karol Kacprzak,* Iwona Skiera, Monika Piasecka, and Zdzisław Paryzek Bioorganic Chemistry Department, Faculty of Chemistry, Adam Mickiewicz University, Ul. Umultowska 89b, 61-614 Poznań, Poland 3.4.2. Sesquiterpene Lactones 3.4.3. Diterpenoids 3.4.4. Polyprenoids 4. Conclusion Author Information Corresponding Author Notes Biographies Acknowledgments References
1. INTRODUCTION Despite enormous progress in the field of the synthetic chemistry involving, for example, catalytic and combinatorial synthesis of a large libraries of compounds, multicomponent reactions and many techniques accelerating the preparation and isolation of organic compounds, natural products are still a fundamental pool of the diverse biological activities.1−4 Their unique molecular architecture is also attractive for designing of numerous specific functional molecules, such as molecular recognition systems (receptors, sensors, chiral stationary phases, tweezers, etc.),5,6 catalysts,7 or specific materials and polymers.8 For this reason, natural product modification, conjugation, or covalent immobilization plays an important role in both pharmaceutical industry and academia, providing over the years, large number of active pharmaceuticals based on alkaloids, steroids, nucleosides, and other biomolecules.9,10 Synthetic tools for a modification of natural products which are currently sought should meet several criteria: preferentially, reaction should be reliable, selective, and easy to perform. Insensitivity to moisture or oxygen is less important but adds to the overall operational simplicity of the procedure. Broad scope, modularity, and orthogonality to other transformation are also expected. Last but not least, high yield and easy isolation of products are other prerequisites. These and other criteria were in 2001 codified by Sharpless,11 who coined the term click chemistry for such favorable processes. The inspiration for the concept of click chemistry (developed originally as a new approach to the synthesis of drug-like molecules, accelerating the drug discovery process) comes from the analysis of Nature biosyntheses where amazing number of diverse structures is forming mainly by the creation of carbon-heteroatom-carbon bonds. In fact, click chemistry has primarily been proposed as a solution reliving synthetic community of making “overinvested”
CONTENTS 1. Introduction 2. Modification of Alkaloids by CuAAC 2.1. Cinchona Alkaloids 2.2. Camptothecin 2.3. Colchicine 2.4. Berberine and Related Isoquinoline Containing Motifs 2.5. Indole Alkaloids (Physostigmine, Reserpine, and Flustramine Analogues) 2.6. 2-Aminoimidazole Alkaloids and Analogues 2.7. Piperidine-Type Scaffolds 2.8. Purine and Related Alkaloids 2.9. Other Alkaloids 3. Modifications of Isoprenoids by CuAAC 3.1. Bile Acids Modification by CuAAC 3.1.1. Bile Acids Dimers, Trimers, Tetramers, and Foldamers 3.1.2. Bile Acid Based Polymers 3.1.3. Bile Acids Macrocycles 3.1.4. Conjugates of Bile Acids with Biologically Active Molecules 3.2. Steroidal Hormones and Cholesterol Modification by CuAAC 3.2.1. Steroidal Hormone Dimers, Trimers, Macrocycles, and Related Systems 3.2.2. Steroid Modification toward New Bioactivities 3.2.3. Cholesterol 3.3. Triterpenoids Modification by CuAAC 3.3.1. Oleane-Type Triterpenoid Acids (Oleanolic, Betulinic, and Glycyrrethinic Acids) 3.3.2. Triterpene Saponins 3.4. Other Isoprenoids Modification by CuAAC 3.4.1. Mono- and Sesquiterpenes © 2016 American Chemical Society
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Received: May 20, 2015 Published: April 26, 2016 5689
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substituent R1 and R2 about 1.1 Å longer as compared to that in the typical amide bond. 1,2,3-Triazoles possess also a much higher dipole moment than the amide bond which actually could enhance peptide bond mimicry due to increasing of the hydrogen bond donor and acceptor ability. Both the N(2) and N(3) triazole atoms act as hydrogen-bond acceptors, whereas the strong dipole may polarize the C(5) proton to such a degree that it can function as a hydrogen-bond donor, similarly to the amide proton. For this reason, the 1,2,3-triazole ring in medicinal chemistry is now often considered as an active pharmacophore rather than a neutral linkage (Figure 1).19 Since 2002, the CuAAC is a subject of thousands of papers and dedicated reviews devoted to general aspects,20−24 mechanism,25,26 drug discovery,19,27−31 modification of sugars,32,33 polymer, and material sciences.34−41 Beside two standard and most robust protocols for CuAAC developed originally by Fokin and Sharpless [in situ Cu(I) formation from CuSO4/Na ascorbate],14 and Meldal (CuI/ DIPEA),15 there are also a number of experimental improvements, including novel catalysts, microwave acceleration, in situ azide formation, continuous flow processing, and copper-free systems (see dedicated review for details42). Alkaloids and isoprenoids constitute two of the largest classes of the natural products which provided a number of the useful drugs since the modern chemistry and medicine have been established. Alkaloids are well-known for their neurotoxic, mindaltering, anticancer properties, and many of them such as quinine, quinidine, opium alkaloids, and camptothecin are in use nowadays in medicine.43 On the other hand, isoprenoids, mainly steroids, play a pivotal role as hormones, contraceptive, antiinflammatory, antiviral, anticancer, and regulatory drugs.44 Smilarly, triterpenoids widely occurring in the plant kingdom serve as a rich pool of anticancer and antiviral drug candidates.45 Isoprenoids, especially higher, such as cyclic di- and triterpenoids possess favorable characteristics involving the chiral and rigid skeleton, multiple functionalities, and unique amphiphilicity. More importantly, many of the alkaloids and isoprenoids are isolated on the large scale from plant sources, so they are considered as renewable and relatively inexpensive materials.46,47 These two groups of natural products until today are a polygon for the drug discovery chemists, providing leads covering virtually all diseases. A systematic SAR study on selected compounds led to the development of many active derivatives or simplified analogues of the alkaloids and steroids introduced to the therapy. Noteworthy, besides in medicinal chemistry, specific classes of the alkaloids such as Cinchona and their derivatives are also frequently used as organocatalysts48−50 and enantiomer separation systems.51 Some steroids, mainly bile acids due to their unique molecular arrangement offering different-sized cavities, diverse binding, and linking sites are attractive scaffolds for the construction of supramolecular devices for molecular recognition and assembly.52−54 An important feature of cholesterol and other less-polar steroids is their easy permeability across biomembranes used often for the construction of drug delivery enhancers.55 In many of these applications, the CuAAC reaction have successfully been used providing a reliable tool for the preparation of new alkaloidal and steroidal derivatives or their hybrids. The CuAAC reaction was also widely applied as an efficient conjugation, linking, immobilization, and macrocyclization method. The intention of this review, which covers more than 240 references is to highlight the CuAAC examples reported
structures, mainly complex natural products. In practice, however, click chemistry reactions were quickly recognized as powerful tools for the modification of existing molecules rather than preparing new, diverse leads (notable exception is in situ click chemistry approach12,13), and this seems to be a dominating trend. One of the earliest examples of click chemistry transformation is Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition between alkynes and azides (CuAAC) reported in 2002 independently by Sharpless14 and Meldal.15,16 The CuAAC quickly gained enormous popularity and became a reference click chemistry reaction (often erroneously considered as click chemistry concept itself). The success of this reaction is also combined with relative simplicity of the introduction of azide or alkyne functionality into organic molecules and their stability toward oxygen, water, and the majority of common reaction conditions in organic synthesis as well as inertness to most of the biological systems. Huisgen 1,3-dipolar cycloaddition is a reaction of an organic azide and terminal (or activated) alkyne forming a 1,2,3-triazole. In the presence of Cu(I), this cycloaddition is highly accelerated and leads exclusively to 1,4-regioisomer of triazole product, in contrast to a long-time known thermal noncatalytic version, which typically provides mixtures of both 1,4- and 1,5regioisomers (Scheme 1).17 Later, Fokin and Jia demonstrated that 1,5-regioisomeric triazoles are the major products when ruthenium catalysts are used instead of Cu(I) for this reaction.18 Scheme 1. General Routes to 1,2,3-Triazoles from Azides and Alkynes
The resulting 1,2,3-triazoles are rigid, stable, and relatively inert heteroaromatics, not undergoing hydrolysis under physiological conditions. More importantly, the 1,2,3-triazole ring can roughly mimic amide bond in respect to the atoms placement and electronic properties (Figure 1). An extra heteroatom in 1,2,3-triazole makes the distance between
Figure 1. Similarity of 1,2,3-triazole ring to amide bond. 5690
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so far in the field of alkaloid and isoprenoid chemistry. A special emphasis is given on the new function or biological activity of the resulting alkaloid or steroid-bearing 1,2,3-triazoles. With the exception of only one review devoted to the analytical application of the 1,2,3-triazoles derived from the selected steroids and triterpenoids, published in 2011 by Ju,56 this subject has not yet been reviewed and individual information is highly dispersed over the existing literature. The presented review covers published material since 2002, until the beginning of 2015.
Meldal procedure employs very mild reaction conditions, with low catalytic amounts of copper(I) iodide (1−5 mol %) in acetonitrile at room temperature. The click immobilization ensured the complete chemical integrity of the multifunctional ligands and offers a controllable loading level of the Cinchona alkaloids (Scheme 3).60 Scheme 3. CuAAC Immobilization of Alkyne-Functionalized Cinchona Alkaloids onto Silica Gel
2. MODIFICATION OF ALKALOIDS BY CUAAC 2.1. Cinchona Alkaloids
Cinchona alkaloids 1−4 comprising well-known antimalarial and bitter quinine 1 or antiarrythmic quinidine 2 are one of the most important classes of alkaloids, with annual production estimated on hundred-tons scale.57 They also occupy a “privileged” position as versatile organocatalysts,48−50 resolving agents, and chiral selectors used in an enantioselective analytics.51 This class of alkaloids is ideally suited for the CuAAC reaction because of an easy installation of the desired alkyne and azide functionality. For example, 10,11-didehydro Cinchona alkaloids 5−8 bearing a terminal acetylene group can be prepared by the bromination of the vinyl double bond followed by subsequent double elimination as described by Hoffmann et al.58 or by optimized chromatography-free large-scale protocol reported by Kacprzak (Scheme 2).59 Due to the remote position of the alkyne group Scheme 2. Synthesis of 10,11-Didehydro Cinchona Alkaloids−Key Alkyne Blocks for CuAAC
The utility of this approach was demonstrated later by the click-immobilization of 10,11-didehydroquinine tert-butylcarbamate 9 onto azido-functionalized silica gel to produce a chiral stationary phase (CSP) 12 for HPLC enantiomer separation (Figure 2). A comparison of the chromatographic behavior of this phase to that of a commercially available with thioetherlinked Cinchona selector (ChiralPak QN-AX) revealed very similar performance characteristics for various model analytes.61 Further studies showed that the phase 12 linked by 1,2,3-triazole exhibits a higher selectivity toward a numerous mandelates, allowing easy analytical and preparative separation.62 The CuAAC reaction was also preferentially used in the immobilization of 3,5-dinitrophenylcarbamoyldidehydroquinine 10 onto azido-silica gel for the preparation of a new donor−acceptor CSP 13. The classical immobilization via radical addition of thiol-
and the 1,2-aminoalcohol domain responsible for the molecular recognition or catalytic function, the resulting 10,11-didehydro Cinchona alkaloids appears to be ideally suited for the CuAACtriggered immobilization. The CuAAC reaction was adapted to the immobilization of various Cinchona alkaloid derivatives bearing an alkyne functionality, such as 5, 9−11 onto azide-modified silica gel surfaces by Kacprzak et al. The developed protocol based on the 5691
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Figure 2. Cinchona alkaloid-derived chiral stationary phases and fluorous reagent linked by 1,2,3-triazole.
Figure 3. Solid phase immobilized Cinchona alkaloid-derived organocatalysts 17−22 with the use of CuAAC reaction.
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Scheme 4. Synthesis of Cinchona Alkaloids-AZT Conjugates Linked by 1,2,3-Triazole
Pericàs.69 The catalysts 20−22 prepared by a simple transformations of 10,11-didehydroalkaloids 5−8 were supported onto polystyrene and efficiently promoted Michael addition of nitroolefins or ethylnitroacetate to carbonyls or enones. More importantly, these heterogeneous catalysts were also successfully used in continuous flow processing, for example quinine-derived catalyst 20 can be operated for 21 h without significant decrease in the conversion. The synthesis of Michael adducts gave remarkable TOF of 1.4−3.2 mmolproduct mmol resin−1 h−1 and an improved enantioselectivity with respect to batch operation.69 On the other hand, 9-hydroxyl group of Cinchona alkaloids can easily be transformed into corresponding 9-O-propargyl ethers, such as 11 and 23−25, giving another site for the CuAAC modification. 9-O-Propargyl ethers of four major Cinchona alkaloids 11, and 23−25 and 10,11-didehydro Cinchona alkaloids 5−8 were used by Celewicz and co-workers as alkyne components for the CuAAC reaction with azidothymidine (26, AZT, Scheme 4). Among the synthesized conjugates 27−30, these derived from 10,11-didehydroquinine 27a as well as 29a− 30a from quinine and quinidine 9-O-propargyl ethers displayed high cytotoxic activity in in vitro studies and remarkable fluorescence.71 9-Azido Cinchona alkaloids 31−34 seem to be another attractive substrate for the CuAAC reaction, providing the corresponding 1,2,3-triazoles, installed in a central part of the Cinchona moiety. The azides 31−34 can be prepared on a small scale using one-step Mitsunobu inversion with HN3 or diphenylphosphoryl azide (DPPA) as an azide source. The more convenient route on large scale is however a two-step sequence involving O-mesylation of alkaloids followed by the nucleophilic substitution of 9-O-mesylates with sodium azide published by Kacprzak et al. (Scheme 5A).72 Homologated azides of Cinchona alkaloids, such as 35−36 reported by Skarżewski et al. further expanded the possibility of the structure
modified silica to the vinyl group of the quinine analogous selector results in uncontrollable side reactions making this preparation unreliable. The difficulties were omitted by applying the CuAAC immobilization. As expected, the 1,2,3-triazolelinked phase 13 allowed a highly selective enantioseparation of the two important group of analytes bearing the electrondonating groups, namely aryloxycarboxylic acids (agrochemicals) and profens (drugs).63 Recently, Lindner et al. reported other clicked Cinchona carbamate CSPs 14 and 15. The Cinchona selectors were in this case linked onto a silica support by using 1,2,3-triazole installed in the carbamate residue (Figure 2).64 Irrespective of the site of the immobilization, all of these CPSs showed a similar performance in the enantioselective separation of the racemic acids. 10,11-Didehydrocinchonidine 7 was also utilized by Soós to create a fluorous-tagged Cinchona reagent 16 by the CuAAC immobilization.65 The CuAAC immobilization was also used for an anchoring of dimeric quinine and quinidine ethers,66,67 as well as 9-amino-(9deoxy)-9-epi-Cinchona alkaloids,68−70 on polymeric support. The immobilized alkaloids 17−22 were developed for the asymmetric synthesis with intention to multiple use (recycling) and facilitate the catalysts removal (Figure 3). The group of Mandoli and Pini reported a series of Cinchona dimeric ethers, such as 17−19 supported onto the Merrifield and ArgoPore resin. The CuAAC immobilization was conducted by Meldal protocol (CuI, DIPEA), and the resultant catalysts were employed in asymmetric dimerization of in situ generated ketenes with very high enantioselectivity (90−97% ee). Moreover, the catalysts were reported to be recycled effectively without significant loss of activity and enantioselectivity over 20 cycles of reaction.66,67 9-Amino-(9-deoxy)-9-epi-Cinchona alkaloids−versatile organocatalysts of many asymmetric additions were also immobilized with the aid of the CuAAC reaction (CuI, tertiary amine) by the groups of Benaglia and Puglisi68,70 and 5693
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Scheme 5. Stereoselective synthesis of Cinchona alkaloid azides−key building blocks for CuAAC reaction
diversification by the CuAAC. These azides were prepared by employing of diastereoselective Corey−Chaykovsky 9-epoxymethylation of cinchoninone 37 followed by ring opening of the intermediate epoxides 38−39 with NaN3/NH4Cl (Scheme 5B).73 Three of such 9-azido Cinchona derivatives 31−32, 34 were used in a feasibility study for the preparation of a library of 1,2,3triazoles 40 using a collection of the commercially available alkynes and the standard CuAAC protocol. High yields and easy isolation of the products 40 (in some cases by the precipitation with water) was noticed (Scheme 6).74
Cinchona azides 31−33 and the homologated azide 35 were also used for the preparation of a novel 1,2,3-triazole hybrids 41 and 42 with the antibiotic polyether ionofores, salinomycin and monensin N-propargylamides 43 and 44, respectively. Despite the dense functionality and possible coordination sites, the use of the standard CuAAC protocol provided the products 41 and 42 in good yields (Scheme 7). The in vitro antiproliferative activity of these conjugates evaluated against three cancer cell lines (LoVo, LoVo/DX, and HepG2) showed that four of the compounds exhibited a high antiproliferative activity (IC50 below 3.00 μM) and appeared to be less toxic and more selective against the normal cells than two standard anticancer drugs.75 An intramolecular thermal 1,3-dipolar cycloaddition of the in situ generated 9-azido-10,11-didehydroalkaloid derivatives 45− 46 was described by Hoffmann. Depending on the configuration at C-9 of the alkaloid and reaction conditions, diverse fused 1,2,3triazoles, such as 47 or 48, with a bis-azahomotwistane skeleton were prepared (Scheme 8). Despite the interesting architecture of these products, no data on their biological screening was given.76 Chmielewski et al. demonstrated an interesting bivalent quinine dimers 49 (Figure 4) as potential inhibitors of P-gpmediated efflux (responsible for the active elimination of drugs from the cell in an ATP-dependent manner, thereby limiting the action of therapeutic agents). Products 49 containing two
Scheme 6. Synthesis of 9-(1,2,3-Triazolo)-Substituted Cinchona Alkaloids 40
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Scheme 7. CuAAC Synthesis of Cinchona Alkaloid-Polyether Ionophore Antibiotic Conjugates
Figure 4. Quinine dimers linked by 1,2,3-triazole designed as P-gp inhibitors.
2.2. Camptothecin
Camptothecin (CPT) 50 is another example of bioactive quinoline alkaloid acting as a topisomerase inhibitor which itself and in the form of numerous derivatives is widely used in anticancer therapy.78 However, due to the poor solubility, substantial toxicity, and low stability of the parent camptothecin, current efforts are undertaken on a development of its novel drug-delivery systems. Many of these are based on an immobilization of camptothecin onto a biocompatible polymer, which upon controllable degradation under physiological conditions provides a mechanism of the drug release. In this context, the CuAAC reaction has been explored as a favorable tool for the preparation of various camptothecingrafted polymers dedicated to cancer therapy. The first report in this field by Emrick et al. involved the immobilization of camptothecin azidoester 51 onto aliphatic polyester matrix 52. Further grafting of the residual alkyne groups in the product 53 was completed with azide-terminated PEG 54 giving the final polyester−camptothecin conjugate 55 with a desirable water solubility. Coupling of the camptothecin azide 51 on 20 mol % loading level (one camptothecin per five monomer repeat units) with the acetylene-functionalized polyester 52 was completed in 48 h using bromotris(triphenylphosphine) copper(I) as a catalyst in dichloromethane. Contrary, the decoration of the resulting polymer 53 with azide-terminated PEG 54 was carried out in water with the use of CuSO4/sodium ascorbate. The resulting polymer 55 gave an estimated molecular weight of 23.5 kDa and showed 18% and 33% of an incorporation of camptothecin and PEG respectively (by weight) as well as narrow polydispersity (PDI 1.20) (Scheme 9).79 A similar approach involving two subsequent CuAAC reactions for the immobilization of the camptothecin azidoester 51 onto polymer, followed by the introduction of azide-terminated PEG 54 was recently reported by the group of Yang. In this case, however, a polyoxetane-type polymer 56 was used as a matrix. The obtained camptothecin conjugates 57 were water-soluble and gave a dosedependent cytotoxicity to human glioma cells and an increased γH2AX foci formation, indicating an extensive cell cycle dependent DNA damage (Scheme 9).80 In a latter work, Emrick reported an elegant approach for the preparation of the camptothecin copolymers 58 involving ATRP (atom transfer radical polymerization) and CuAAC in a one-pot reaction format. The zwitterionic poly(methacryloyloxyethyl phosphorylcholine) was selected as a polymeric support due to its high biocompatibility and a low protein adsorption. The preparation of 58 involved the one-pot reaction of the methacryloyloxyethyl phosphorylcholine 59, the TMS-protected alkyne monomer 60, one of three camptothecin-derived azides 61 differing in the spacer length catalyzed by ethyl 2bromoisobutyrate 62, CuBr, and bipyridine (bpy) (Scheme 10). All of the obtained conjugates 58 were synthesized with a controllable, high weight percent drug loading (up to 14%), showed excellent solubility in water (>250 mg/mL), and a
Scheme 8. Intramolecular Huisgen 1,3-Cycloaddition of 9Azido-10,11-didehydro Cinchona Alkaloids
quinine molecules were linked by a varying length spacer in a simple manner by using the CuAAC reaction. Such obtained quinine dimers 49 were found to act as P-gp inhibitors, with best compounds exhibiting a low micromolar efficacy and having 10 or 12 methylene units flanking the triazole ring (n = 4 and 6).77 5695
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Scheme 9. Two Routes of CuAAC-Triggered Immobilization of Camptothecin onto Polymeric Support
a set of its 1,2,3-triazole derivatives 67 by the microwave-assisted CuAAC. The site of the modification of 66 was the carbon-7, which on the basis of SAR studies can be affected without diminishing the biological activity. The key azide 68, can readily be prepared from the commercially available colchicine in a fourstep route involving initial Boc protection, removal of the acetyl group, and subsequent Boc deprotection followed by the diazotransfer reaction (Scheme 12). The evaluation of the triazoles 67 revealed their potential as antitumor agents for further development.84 Other related 1,2,3-triazolo colchicinoids, such as 69 were also reported by the same group.85 An interesting concept for the reduction of systemic toxicity and improvement of biodistribution of colchicine was reported by the group of Kuznetsova and Schmalz. Colchicine and allocolchicine were transformed into lipophilic triazoles 70 and 71, respectively, in a two-step sequence involving the CuAAC reaction with propargyl alcohol and subsequent esterification with palmitic or oleic acids (Figure 5). Biological evaluation allowed for the conclusion that the active are only the colchicine derivatives 70, in contrast to less active allocolchicine derivatives 71. Among the products, palmitic ester 70 showed a 3-fold increase in antimitotic activity as compared to parent alkaloid (whole cell assay) but also lower affinity to the colchicine binding site in tubulin.85 In further studies, esters 70 were also encapsulated in liposomes prepared by the extrusion of egg phosphatidylcholine, yeast phosphatidylinositol, and palmitic or oleic esters. The resultant liposomes screened against a panel of
narrow polydispersity index (PDI 1.25−1.36). Camptothecin release from these copolymers was dependent on the linkage type installed between polymer backbone and the pendant drug. The anticancer activity of these polymers was tested against human breast (MCF7), ovarian (OVCAR-3), and colon (COLO 205) cancer cells, and the products exhibited cytotoxicity at IC50 values higher than the native camptothecin in the range of 2.3− 6.7 μM.81 A library of 7-triazole-substituted camptothecin 63 was prepared by Huang et al. by employing the CuAAC reaction. A readily accessible 7-ethynylcamptothecin 6482 served as an alkyne component and was prepared by Sonogashira coupling of the readily available 7-chlorocamptothecin 65. Alkyne 64 reacted further with a series of simple azides under the standard CuAAC protocol, providing the respective triazoles with very good yields (Scheme 11). After deprotection of camptothecin ester final products 63 were assessed for their cytotoxicity against A549, HCT-116, HT-29, LoVo, and MDA-MB-231 cell lines. Three of them, with R = Bu, Bn, and −(CH2)4COOMe showed in vitro very good activity and all of the products 63 retained the inhibitory potency toward Topo I.83 2.3. Colchicine
The well-known toxic alkaloid colchicine 66 originally extracted from plants of the genus Colchicum is an attractive scaffold for design of anticancer leads due to its remarkable tubulin-binding activity. Colchicine was used by Schmalz et al. for the preparation 5696
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Scheme 10. Preparation of Camptothecin Copolymers 58 by One-Pot CuAAC and ATRP Reaction
Scheme 12. CuAAC Synthesis of Colchicine 1,2,3-Triazole Derivatives at C-7
Scheme 11. Synthesis of 7-(1,2,3-Triazole)-Substituted Camptothecin Figure 5. Colchicine and allocolchicine lipophilic triazoles prepared by CuAAC reaction.
formulation of ester 70 bearing the oleoyl chain inhibited cell proliferation more efficiently than the unbounded ester 70.86 Fedorov et al. designed a series of dyads 72 containing two antimitotic agents, colchicine and tubulizine, linked by 1,2,3triazole, with intention of increasing their individual anticancer activity. The preparation of 72 involved the CuAAC reaction of azide-modified colchicine congeners 73 with acetylene-decorated tubulizine 74 and gave the products in a good yield. The desired colchicine azides 73 bearing linkers of various lengths were conveniently synthesized from colchicine in four steps, whereas the alkyne-functionalized tubulizines 74 were prepared in two- or three-step route starting from cyanuric chloride (Scheme 13). All dyads 72 displayed a remarkable cytotoxic activity (IC50 = 0.60−2.93 μM) toward the HBL100 human mammary cell line. Although all of the triazoles 72 were more active than tubulizine, none exceeded the potency of deacetylcolchicine. Several compounds of this series were also substoichiometric inhibitors of microtubule assembly.87
four human tumor cell lines confirmed the preservation of the cytotoxicity of colchicine derivatives and showed that liposomal 5697
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multivalent inhibitors of acetyl- and butyrylcholine esterases (AChE and BChE) and β-amyloid aggregation inhibitor (these factors are responsible for the neurodegenerative cascade of Alzheimer’s disease). The synthetic route to 76 involved the conversion of 75 to berberine azides 77 via partially demethylated berberrubine 78. The desired alkynes, namely Npropargyl-substituted tertiary amines 79 were obtained in the reaction of secondary amines with propargyl bromide. The CuAAC reaction with CuSO4, sodium ascorbate in DMF afforded the desired berberine-triazoles 76 (Scheme 14). The screening of this library allowed for the identification of a few highly active compounds. For example 76, bearing a diisopropylamino group at the 4-position of the triazole ring, displayed inhibitory activity with an IC50 value of 0.044 μM against AChE (and selectivity toward AChE), whereas 76, with a butyl substituent, showed both good inhibitory activity against AChE (IC50 value of 0.20 μM) and the highest potency of βamyloid aggregation inhibition.88 This study was recently extended by the group of Jin and Yan, who prepared a library of berberine triazoles 80 with reverse connectivity of the triazole group for cytotoxicity screening. Direct O-propargylation of berberrubine 78 led to O-propargylberberine 81, which in the subsequent CuAAC reaction with 33-substituted benzyl azides gave the corresponding triazoles 80 (Scheme 14). All of the products were assessed for the anticancer activity against three human cancer cell lines (MCF-7, SW-1990, and SMMC-7721) and the HUVEC line (normal human umbilical vein endothelial cell). It was found that most of the derivatives displayed higher anticancer activities against the MCF-7 as compared with parent berberine. Compound 80 with 4-tert-butyl substituent in the phenyl ring was identified as the most potent against the SW1990 and SMMC-7721 cell lines with IC50 values of 8.5 and 11.9 μM, respectively.89 Pancratistatin 82 and related isoquinoline alkaloids isolated from the Amarillydaceae family exhibit a broad spectrum of
Scheme 13. Colchicine-Tubulizine Dyads Linked by 1,2,3Triazole
2.4. Berberine and Related Isoquinoline Containing Motifs
Berberine 75 was used as a scaffold for the construction of a new class of triazole-containing derivatives 76 using click chemistry by He and Li. The intention of this work was to develop new Scheme 14. Synthesis of Berberine-1,2,3-Triazole Library
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against Alzheimer’s disease. However, due to its low bioavailability and a narrow therapeutic window, better candidates are sought. (−)-Physostigmine analogs 87 and 88 substituted at C5 of the alkaloid core with the 1,2,3-triazole ring were prepared by Qin et al. The desired enantiomer of the alkaloid azide 89 was synthesized de novo using an organocatalytic cascade reaction as the key step (99% ee after single recrystallization). Its CuAAC reaction with a variety of alkynes provides a library of the corresponding triazole products 87 and 88 in good yields (Scheme 15). No data of the biological activity were reported in this work.93
biological activities, including anticancer, antiviral, and antiparasitic. Since the synthesis of the original alkaloid is difficult, a number of its simplified analogues were prepared with intention of retaining of the activity or identifying the pancratistatin pharmacophore. For example, Gonzalez et al. demonstrated pancratistatin surrogate 83 with a fused 1,2,3-triazole ring installed in the place of the aromatic ring A of the parent alkaloid (Figure 6). In this case, thermal noncatalytic intramolecular Huisgen cycloaddition was employed for the synthesis of 83. No data regarding their activity was provided.90
Scheme 15. Physostigmine Analogs Substituted at C5 with the 1,2,3-Triazole
Figure 6. Mimicks of isoquinoline alkaloids bearing 1,2,3-triazole motif.
Another 1,2,3,4-tetrahydroisoquinoline derivative containing a 1,2,3-triazole moiety of general structure 84 was prepared by Pingaew et al. in the synthetic sequence involving a modified Pictet-Spengler reaction and the CuAAC for the installation of the triazole ring (Figure 6). The products were screened toward antiproliferative activity against four cancer cell lines (HuCCA-1, HepG2, A549, and MOLT-3) and some of them exhibited a good level of cytotoxicity. For example, ester 84a was shown to be the most potent compound against HuCCA-1 (IC50 = 0.63 μM) and A549 (IC50 = 0.57 μM) cell lines, whereas triazole 84b with ptolyl substituent displayed the most potent activity against HepG2 cells (IC50 = 0.56 μM) and exceeded the activity of drug etoposide or doxorubicin without affecting normal cells.91 A general, modular and simple synthesis of 1,2,3-triazoles fused with five-, six-, seven-, and eight-membered benzoheterocycles, including isoindoline, tetrahydroisoquinoline 85, benzoazepine, and benzoazocine was reported by Chowdhury et al. The synthesis is based on a one-pot reaction of readily accessible 2iodobenzylazides with alkynes in the presence of palladium and copper acting as a dual catalytic system (Figure 6).92
A similar physostigmine analogs 90 (Scheme 15) bearing 1,2,3-triazolyl at C-5 and having the methyl group at C-3a were reported by the group of Zhang, with the intention of developing novel anticholinesterase activity leads. The triazoles 90 with heterocyclic substituents in the 1,2,3-triazole moiety showed an increase in both AChE and butyrylcholinesterase (BChE) inhibitory activities.94 Another example of indole alkaloid reserpine was used by Sierra et al. for the preparation of a series of reserpine homodimers 91 and 92 linked by 1,2,3-triazoles. Their
2.5. Indole Alkaloids (Physostigmine, Reserpine, and Flustramine Analogues)
An indole alkaloid (−)-physostigmine 86 is one of the earliest inhibitor of acetylcholinesterase used as a therapeutic agent 5699
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Scheme 16. Reserpine Homodimers Linked by 1,2,3-Triazoles
(possessing wide antimicrobial activity) as a scaffold for the CuAAC synthesis of the 18-member library of pyrroloindoline 1,2,3-triazole amides 98 and 99. A synthetic alkyne functionalized pyrroloindoline mimic 100 of flustramine reacted with a series of 18 diverse azides followed by the deprotection of the pyrrolidine nitrogen atom (Scheme 17). The produced library was screened toward the ability to modulate biofilm formation against strains of Gram-positive and Gram-negative bacteria such as A. baumannii, E. coli, and methicillin-resistant Staphylococcus aureus (MRSA) and provided several nontoxic compounds with a low micromolar IC50 values. For example, compounds 99 bearing p-alkylphenyl group (C5−C7) exhibited a high activity against MRSA and inhibited the biofilm formation of methicillin
preparation began with the direct propargylation of reserpine 93 by propargyl bromide providing two regioisomeric products 94 and 95 in 63 and 30% yield, respectively. After the separation, each reserpine alkyne was converted into respective dimers tethered by a bis-triazole linker by using two diverse diazides 96 under the standard CuAAC reaction condition (Scheme 16).95 Application of these structurally interesting derivatives were not reported. One of the most urgent problems in the therapy of microbial infection is a combating the biofilms forming bacteria (which are estimated to be responsible for ca. 75% of infections that occur in the human body). Work toward this goal was reported by group of Melander who used the flustramine family of alkaloids 97 5700
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Scheme 17. Pyrroloindoline 1,2,3-Triazole Amides 98 and 99 as Mimics of Flustramine Alkaloid
Figure 7. 1,2,3-Triazolyl tryptolines 102 and 103 as mimicks of bisindole alkaloid Ochrolifuanine E 101.
Scheme 18. Oroidin Alkaloid Mimicks with Amide Group Replaced by 1,2,3-Triazole Bioisoster
sensitive strain Staphylococcus aureus, giving IC50 values ranging from 6.6 to 32.0 μM.96 Ochrolifuanine E 101 is a bis-indole alkaloid identified in plants of the species Dyera costulata used in Thai herbal medicine. A virtual screening procedure reported by the group of Vajragupta showed that this alkaloid is a good candidate for inhibitor of β-secretase (BACE1). This enzyme is responsible for the formation of amyloid peptides from the amyloid precursor protein, and thus is a promising target for development of drugs for Alzheimer’s disease. Analysis of the docking studies of the parent alkaloid revealed that tryptoline (2,3,4,9-tetrahydro-1Hpyrido[3,4-b]indole is a key pharmacofore responsible for the binding with the enzyme. Further considerations led to the design of the library of the 1,2,3-triazolyl tryptoline derivatives 102, among which 22 most promising candidates (selected from the docking analysis) were prepared by using the CuAAC reaction. Products 102 screened for the inhibitory action against BACE1 allowed the identification of one potent inhibitor 103 (IC50 = 1.49 μM), which was also 100 times more selective to BACE1 than Catepsin D (Figure 7).97 2.6. 2-Aminoimidazole Alkaloids and Analogues
2-Aminoimidazole alkaloids from the oroidin family, such as 104, are another antibiofilm natural products. Melander and coworkers used them as a platform to design the synthetic antibiofilm lead 105, where an amide group was replaced by 1,2,3-triazole bioisoster. In a series of papers, several libraries of 2-aminoimidazole 1,2,3-triazoles such as 106−108 have been prepared using the CuAAC and screened. Some of the synthesized compounds were found to efficiently inhibit the biofilm formation by MRSA at low-micromolar concentrations or inhibit and disperse Acinetobacter baumannii biofilms, being more active as compared to the naturally occurring biofilm dispersant cis-2-decenoic acid (Scheme 18).98−100 Naamine A 109 and isonaamine A 110 were another example of 2-aminoimidazole type of active marine alkaloids which served as an inspiration for design of the more accessible mimics 111
and 112 with the antibiofilm activity. In an approach demonstrated by Blache et al., the imidazole core of these alkaloids was replaced by the 1,2,3-triazole ring incorporated by the CuAAC (112, 1,4-regioisomers) or RuAAC (111, 1,5regioisomers) reaction (Scheme 19). Among 22 compounds prepared and screened for their biofilm inhibitory activity against two strains of Gram-negative bacteria, four triazoles acted as nontoxic inhibitors of the biofilm formation without the effect on the bacterial growth.101 5701
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Scheme 19. Naamine A and Isonaamine A Mimics 111 and 112 Prepared by CuAAC Reaction
Scheme 20. Routes to 1,2,3-Triazole-Substituted 3Aminopiperidines 113 and 1,2,3-Triazole-Substituted 3Hydroxypiperidines 114
TMS group. The resulting alkyne 120 was then used for the set of the CuAAC reaction with simple azides providing the products 114 in moderate to good yields (Scheme 20).103 Another approach to the 1,2,3-triazole-substituted piperidines 121 and 122 demonstrated by Shinde et al. was based on the introduction of azido group in position 4 of the piperidine ring by a simple transformation of N-Boc-protected piperidinone 123. The azide 124 was then reacted with ethyl propiolate or propargyl alcohol in the presence of CuI giving the respective products 121 and 122. Further modification of these products led to derivatives 125 and 126 which showed a remarkable antifungal acitvity (Scheme 21).104,105 Wang demonstrated a conceptually different approach to the preparation of 3-azidopiperidines 127 based on one-pot intramolecular cyclization of an unsaturated amines 128 (Scheme 22). As expected, the resultant azides, such as 129 prepared from the amine 130 could be further converted into the corresponding 1,2,3-triazole 131 by means of the standard CuAAC reaction.106
2.7. Piperidine-Type Scaffolds
The piperidine ring is a common structural motif in numerous alkaloids and one of the privileged moiety in medicinal chemistry. An adaptation of the CuAAC to the synthesis of a library of 1,2,3triazole-substituted 3-aminopiperidines 113 and 1,2,3-triazolesubstituted 3-hydroxypiperidines 114 was demonstrated by several groups. In the first approach reported by Christoffers, a racemic protected piperidine 115 underwent a nucleophilic aziridine ring opening with NaN3 on the multigram scale giving two regioisomeric 116. This chromatographically inseparable mixture was subjected to the CuAAC reactions with ten different alkynes, and the resulting products, orthogonally N-protected (Boc and Cbz) trans-4-(1,2,3-triazol-4-yl)-substituted 3-aminopiperidines, were obtained as a mixture of regioisomers 117 and 118 (with typical ratio ca. 6:1 for 118). Isolation of the regioisomers and their subsequent deprotection afforded free amines 113 (Scheme 20).102 trans-4-Triazolyl 3-hydroxypiperidines 114 were prepared by Haug et al. by the regioselective opening of the racemic epoxide 119 with TMS-acetylene followed by the deprotection of the
2.8. Purine and Related Alkaloids
6-Mercaptopurine 132, a synthetic drug related to naturally occurring purine alkaloids, was used by Da Silva for the synthesis of a series of novel mono- and bis-1,2,3-triazolyl derivates 133 and 134. N- and S-propargylation of 132 leads to mono- or dipropargyl derivatives 135 and 136 which undergo the CuAAC reaction with azidoacetic acid (Scheme 23) and methyl 3-β-azido 5702
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ratio of inhibition parasite multiplication than the common antimalarial drug chloroquine.107 A purine as a scaffold was also used for the design of novel neuroprotective agents 137 containing a 1,2,3-triazole ring and fluoroaromatic groups. The synthesis of that library began with a two-step decoration of the commercially available 2,6-dichloropurine 138 with the alkyne group followed by the CuAAC reaction of the resulting alkyne 139 with in situ generated benzyl azides. The triazoles 137 were screened for neuroprotective effects using fluorescence electron microscopy. One of the compound containing o-fluorophenylmetyl group was found to exhibit a neuroprotective effect comparable to that of Flavopiridol and Roscovitine, two state of the art cyclindependent kinase (CDK) inhibitors against the amyloid β (Aβ)-induced neurotoxicity (Scheme 23).108 A series of conjugates 140 and 141 containing pharmacologically privileged heterocycles such as pyrazolo[3,4-b]pyridine and pyrimidine containing trifluoromethyl group linked by 1,2,3triazole were reported by Narsaiah et al. The synthesis based on the CuAAC reaction catalyzed by CuI of 3-azido-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine 142 with N- or Opropargyl pyrimidine derivatives 143−144, respectively. The resulting intermediates were N-alkylated with different alkyl halides to provide the expected conjugates 140 and 141 (Scheme 24). The library screened for cytotoxicity against four human cancer cell lines, such as A549, MCF7, DU145, and HeLa, allowed identification of few leads with a remarkable activity, for example, 141 with R = propargyl or long alkyl substituents.109
Scheme 21. Synthesis of 1,2,3-Triazole-Substituted Piperidines 125 and 126
2.9. Other Alkaloids
Cyclopamine 145 a natural steroidal alkaloid isolated from Veratrum californicum is a potent inhibitor of Hedgehog signaling pathway, which an aberrant activation is related to many types of cancers. Unfortunately, cyclopamine itself is also toxic to normal tissues and has poor aqueous solubility. For this reason, design of water-soluble prodrugs of this alkaloid programmed to deliver cyclopamine selectively in the vicinity of the tumor is an important task. One of the solutions was demonstrated by Papot et al., who prepared glucuronide prodrug 146 designed to release cyclopamine in the presence of β-glucuronidase, an enzyme that is detected at a high level in necrotic parts of numerous tumors. Besides the glucuronic acid unit, 146 possesses also a hydrophilic PEG-type side chain introduced via the CuAAC on the selfimmolative linker. This product, after the activation by βglucuronidase, exhibits improved kinetics of drug release and restores its antiproliferative activity tested on U87 glioblastoma cells (Scheme 25).110 Cyclopamine 145 was also used for the synthesis of glycoconjugates 147 by using the CuAAC reaction as reported by Chang. N-Propargylcyclopamine 148 served as an alkyne and reacted with a collection of 11 anomeric peracetylated azidosugars 149. The library of the corresponding 1,2,3-triazoles 147 was obtained with good yield using in situ generated Cu(I) ions and sonication. Deacetylation of the resulting 1,2,3-triazoles gave the corresponding conjugates 147, which were subjected to a screening against the lung cancer cell. Compound 150 with Lrhamnose residue exhibited slightly improved cytotoxicity having IC50 33 μM as compared to the parent cyclopamine (IC50 49 μM) (Scheme 26).111 The CuAAC reaction was also used for the preparation of fluorophore-labeled cytotoxic marine alkaloid discorhabdin C 151 for an investigation of its cellular target. The key alkyne derivative 152 (showing the bioactivity comparable with the
Scheme 22. Preparation of 3-Azidopiperidines 127 and 129 and Their Further Conversion into the Corresponding 1,2,3Triazole 131 by CuAAC Reaction
cholanoate. Selected products of these library, for example 133− 134 showed a remarkable antimalarial activity in vitro by a higher 5703
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Scheme 23. Purine-Derived 1,2,3-Triazoles
Scheme 24. Pharmacologically Privileged Heterocycles, Pyrazolo[3,4-b]pyridine and Pyrimidine Linked by 1,2,3Triazole
Scheme 25. Water-Soluble Glucuronide Prodrug of Cyclopamine 146
parent discorhabdin) has been prepared by the reaction of discorhabdin C with 2-bromo-N-propargylacetamide. Its conjugation with dansyl or lissamine azides afforded the desired products 153a−153b in good yield (Scheme 27).112 Glycoconjugates of phenanthroindolizidine alkaloids were designed for targeting tobacco mosaic virus (TMV) by Wang et al. The conjugation of (S)-6-O-desmethylantofine 154 and 14hydroxytylophorine 155 with sugars was accomplished in three different ways. One of them used formation of the 1,2,3-triazole as the linker for the binding of suitably O-propargylated alkaloids 156 and 157 with three different monosugar units (Scheme 28). The resultant glycoconjugates 158 and 159 showed an improved water solubility, but their activity was moderate as compared with
the highly active conjugates linked by the simple glycosidic bond.113 5704
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biological evaluation of a series of N-substituted-1,2,3-triazole murrayafoline A derivatives 163. The products 163 were synthesized using the CuAAC reaction of azido-derivative of Murrayafoline A 164 and collection of diverse alkynes (Scheme 30). Biological screening involved the testing of the antiinflammatory action and two triazoles 163 (R = −CH2NH2 and −CH2OH) exceeded the activity of unmodified Murrayafoline A, efficiently inhibiting the production of cytokines IL-12 p40 and IL-6 as well as TNF-α.115
Scheme 26. CuAAC Synthesis of Cyclopamine Glycoconjugates
3. MODIFICATIONS OF ISOPRENOIDS BY CUAAC Isoprenoids constitute a large class of natural product originating from condensation of five-carbon atom precursors (isopentenyl and dimethylallyl pyrophosphate). Depending on the number of isoprene units which are basic building block of all isoprenoids, they are classified as mono-, sesqui-, di-, sester-, tri-, tetra-, and polyterpenes. Both rich structural diversity and biological activity of isoprenoids, especially steroids and their subclasses including bile acids and steroidal hormones, as well as triterpenoids make them a primary pool for biological activity screening and source of molecules for further modification and conjugation in medicinal chemistry.44,45,116,117 An important benefit of isoprenoids is their wide distribution in nature as well as industrial availability of many of them in enantiomerically pure forms.
Scheme 27. Fluorophore-Labeled Cytotoxic Marine Alkaloid Discorhabdin C Prepared by CuAAC Reaction
3.1. Bile Acids Modification by CuAAC
Bile acids are privileged building blocks for supramolecular chemistry.118 In this context, synthesis of bile acids dimers,119 trimers and polymers,120 and respective macrocyclic cholaphanes is widely explored due to diverse properties and uses, including inclusion, miscellar, detergent, and liquid crystals capability,121 pharmacological action and drug delivery,55,122−124 as well as catalytic applications.125 Furthermore, dimeric steroids and cholaphanes were also used as molecular umbrellas and artificial receptors for small molecules and ions.52−54,117,118 Bile acids are ideally suited for the CuAAC reaction because of easy introduction of azide or alkyne functionalities, typically by esterification, amidation, or propargyl ether formation. Selective addressing of an available hydroxyl groups in the steroidal scaffold or side chain carboxylic function may lead to highly diverse architectures. On the other hand, simultaneous installation of both azide and alkyne functionalities in a single bile acid molecule give opportunity to prepare macrocycles or polymers. Further tuning of the polarity, solubility, or conjugation with another molecule of such azide/alkyne decorated bile acid building blocks or bile acid 1,2,3-triazoles could typically be achieved by using an unmodified hydroxyl or carboxylic group. All of these advantages of bile acids as well as their broad availability led to an intense synthetic work based on the CuAAC reaction. Chenodeoxycholic acid 165 is the most potent physiological ligand for farnesoid-X-receptor (FXR), which is responsible for controlling bile acid synthesis and homeostasis, liver regeneration, and tumorigenesis as well as cholesterol gallstone formation. This compound was used by Cheng, Zhang et al. for construction of a simple imaging agent 166 by coupling of 18F radiolabeled marker to the bile acid side chain. For this purpose chenodeoxycholic acid N-propargylamide 167 was prepared conveniently in one step followed by CuAAC reaction with 18Flabeled 2-fluoroethylazide giving desired product 166 in 73% yield (Scheme 31). This 1,2,3-triazole linked radiotracer was shown to maintain lipophilicity of parent bile acid and a high
A series of 2β-alkynyl 160 and 2β-(1,2,3-triazolyl)-3β(aryl)tropanes 161 were synthesized by Carroll et al. as cocaine analogues and screened toward affinity of dopamine, serotonin, and norepinephrine membrane transporters by using competitive radioligand binding assays. All prepared compounds, including two triazoles 161a−161b obtained from the alkyne intermediate 160 by using the CuAAC reaction, were found to exhibit nanomolar or subnanomolar affinity for the dopamine transporter (DAT)(Scheme 29).114 Murrayafoline A 162 is a simple carbazole alkaloid isolated from the root of various species of the genus Murraya. Despite having a simple structure, Murrayafoline A exhibits a wide spectrum of biological activity, involving fungicidal and apoptosis induction among others. Thuy et al. reported synthesis and 5705
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Scheme 28. 1,2,3-Triazole-Linked Glycoconjugates of (S)-6-O-Desmethylantofine 154 and 14-Hydroxytylophorine 155
Scheme 29. Cocaine Analogues, 2β-Alkynyl 160 and 2β(1,2,3-Triazolyl)-3β-(aryl)tropanes 161
Scheme 31. Chenodeoxycholic Acid Based Imaging Agent 166 Containing 18F Radiolabeled Marker Introduced by CuAAC Reaction
Scheme 30. CuAAC Synthesis of N-Substituted-1,2,3-Triazole Murrayafoline A Derivatives
metabolic stability in vitro and in vivo. PET/CT imaging in nude mice demonstrated a rapid uptake of the tracer into liver tissue with uniform distribution of radioactivity in the liver. Thus, tracer 166 was suggested to constitute a novel imaging tool for detection of abnormalities in the liver.126 3.1.1. Bile Acids Dimers, Trimers, Tetramers, and Foldamers. Pore and Ju independently showed the highyielding preparation of a series of 1,2,3-triazole-tethered bile acid dimers, such as 168−171, involving head-to-tail, head-to-head, and tail-to-tail and other types of linkage (using C-3, C-11, and C-24 positions of cholic and deoxycholic acid).127−129 The deoxycholic acid dimer 169 (R = H) was recently synthesized as a 3,3′,12,12′-tetra-O-acetyl derivative by Paryzek et al.130 Later, Pore expanded his work for the synthesis of other bile acids dimers, trimer 172, and tetramer 173 (Figure 8). These compounds can solubilize the polar cresol red dye in a nonpolar 5706
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Figure 8. Examples of 1,2,3-triazole-tethered bile acid dimers involving head-to-tail, head-to-head, and tail-to-tail and other type of linkages prepared by CuAAC reaction.
fluorescence intensity could than be used for the detection of heavy metal ions with the detection limit of about 1 μM in aqueous media.132 A simple deoxycholic acid based bis-1,2,3-triazole tweezers 179 bearing two aromatic aldehydes have been prepared by Pandey and Kumar (Figure 9). These compounds showed high selectivity and sensitivity toward the Hg2+ ion compared to other transition metals with 1:1 binding stoichiometry and engagement of both 1,2,3-triazole and aldehyde group in the metal recognition process.133 The CuAAC reaction has also been used by Zhao for the preparation of a linear cholic acid based foldamers 180 designed as an artificial transporter of polar molecules across lipid membranes. Their modular synthesis based on the CuAAC reaction between an azide-functionalized cholate trimer 181 equipped with a pyrene unit as a reporter group and three diverse dialkyne linkers. The cholate tethers play an important role in transport and binding events making in solution poorer folders faster transporters across membranes and vice versa (Scheme 33).134 3.1.2. Bile Acid Based Polymers. Logic extension of the reports on small linear cholate oligomers toward synthesis of linear polymers such as 182 was realized by Pandey et al. Starting from three bile acids, a three step preparation gave the necessary bifunctional monomers 183 containing both azide and alkyne functionality. The CuAAC reaction led efficiently to the corresponding polymers 182 of molecular weight in the range
medium and exhibited a reverse micellar behavior in a nonpolar solvent. Further analysis showed that cholic acid based dimer was the most efficient in an encapsulation of the dye that was attributed to the adaptation of a possible cis-conformation (other nomenclature C-conformer) of this type of dimer.128 An another example of tripodal bile acid architectures 174 and 175 based on a functionalized triphenylphosphine oxide as a core was reported by Beletskaya et al. In this case, either cholic or deoxycholic acids were stereoselectively transformed into the respective 3α or 3β-azides 176, which were then reacted with trispropargyl ester of 4-carboxytriphenylphosphine oxide 177 under the standard CuAAC condition. Subsequent amidation of the carboxylic group in 174 with taurine led to the amides 175 (R = −NH(CH2)2SO3Na) in good yield (Scheme 32). The aggregation behavior of these products were studied in aqueous media by different methods, including dye solubilization, dynamic light scattering, NMR, and AFM. Unexpectedly, it was found that only 3α-azides of bile acids gave the products 175a−175b, which were capable to form organogels and aggregate at micromolar concentration.131 Tris(O-propargyl)pentaerythriol scaffold and 3β-azido cholic acid 176 were used for construction of similar trimeric molecular pockets such as 178 based on the CuAAC reaction as reported by Zhu (Figure 8). This product could solubilize a highly hydrophobic pyrene in aqueous solution, and the resulting host−guest complex is sensitive to heavy metal ions, which can coordinate to the 1,2,3-triazole ring. The decrease in the 5707
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Scheme 32. Tripodal Bile Acid Architectures 175 Linked by 1,2,3-Triazole
Figure 9. Bile acid based molecular pockets 178 and tweezers 179 assembled by the CuAAC reaction.
the intermediate macrocycle 190 with good yield (50%). Its further methylation and anion metathesis gave the desired sensor 188 as a PF6− salt (Scheme 35). More acidic as compared to the 1,2,3-triazole ring protons of 1,2,3-triazolium moieties act as a better hydrogen bond donor (together with methylene protons) and are primarily responsible for anion recognition, whereas a cavity size adds to the observed selectivity toward chlorides.138 Another example of a simpler cyclic receptor 191 containing the 1,2,3-triazolium moieties and showing a moderate affinity toward phosphates was repoted by the same group (Scheme 35).139 Two types of more conformationally flexible secosteroidal macrocycles with an opened ring C (12,13 secocholate) 192 and ring B (7,8-secocholate) 193 were reported by Ibrahim-Ouali and Hamze. The secosteroidal azide and alkyne decorated components 194 and 195 for the CuAAC macrocyclization were obtained by multistep degradative transformation of propargyl cholate 196, whereas the cyclization was performed by the standard CuAAC reaction yielding 66% and 62% of macrocycles 192 and 193, respectively (Scheme 36).140 Cyclic cholic acid−peptide conjugate 197 bearing antilysosyme CDR3 fragment (Asp-Ser-Thr-Ile-Tyr-Ala-Ser-Tyr-TyrGlu-Ser) was prepared by Madder et al. by using a solid phase approach (Figure 11). The steroidal scaffold was decorated by desirable peptide chains at position 3 and 12, whereas its side chain was used for the covalent attachment to the resin bead (Tentagel). The CuAAC reaction was employed in this case for the introduction of alkyne-derived peptide fragment at azidoterminated linker installed at the 3α-amino group of cholate. The final ring closure of the peptide chain was completed by using macrolactamization with HCTU as a coupling reagent. Although the reported peptidosteroid 197 did not show the binding to
of 33−97 kDa and low polydispersity (PDI ∼ 1.25) (Scheme 34). It is worth noting that the resulting polymers were shown to stabilize silver nanoparticles and exhibited also selectivity toward iodide ions allowing its colorimetric sensing.135 Conceptually similar polymers 184 with internal polyester and polyamide linkage were synthesized in four steps from cholic acid and characterized by Zhu (Scheme 34).136 3.1.3. Bile Acids Macrocycles. Synthesis of a series of conformationally flexible cholaphanes 185−187 employing the single CuAAC reaction as a ring closure step of bis(cholane)24,24′-diazides, bis(cholane)-24,24′-dipropargyl esters, or azide/ alkyne litocholic and deoxycholic acid derivatives was demonstrated by the group of Lukashev (Figure 10).137 An interesting example of cholaphane 188 designed as an anion sensor which exhibits high affinity toward chlorides (Ka = 3700 M−1) was reported by Pandey et al. The CuAAC macrocyclization of a suitable bifunctional monomer obtained in a short synthetic sequence from deoxycholic acid 189 led to 5708
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Scheme 33. Linear Cholic Acid -Based Foldamers 180 Linked by 1,2,3-Triazole Designed as an Artificial Transporter of Polar Molecules Across Lipid Membranes
Scheme 34. CuAAC Synthesis of Cholic Acid Based Linear Polymers 182
lysosyme, the presented approach seems to be general for the synthesis of a cyclic peptide decorated cholates.141 Another example of a solid-supported bifunctional clickable building block 198 decorated with both alkyne and azido groups derived from cholic and deoxycholic acid was reported by
Madder. The structure 198 may offer a new platform for the solid-phase preparation of a dedicated heterodipodal bile acidpeptide conjugates with defined spatial arrangements by the CuAAC ligation (Figure 11).142 5709
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minimum inhibitory concentrations (MIC) ranging from 3.12 to 6.25 μg/mL.143 Another example is a bioconjugation of cholic and deoxycholic acids with β-lactam dimers by using 1,2,3-triazole linker toward novel antibiotic leads. The modular synthesis based on the CuAAC reaction gave the library of products 201 in good yield. Antimicrobial activity screening resulted in an identification of several potent conjugates 201 which showed antifungal activity against C. albicans or C. neoformans (in some cases the activity was higher than that of the reference fluconazole). In addition, other compounds of this series were active against plant pathogen F. oxysporum comparable to amphotericin B inhibitory activity as well as against Y. lipolitica or Staphylococcus aureus (showing low-micromolar level of MIC) (Scheme 37).144 On the other hand, monomeric β-lactams-bile acids conjugates 202 linked by 1,2,3-triazole were planned as a mimic of the antibacterial drug Tazobactam 203. These compounds were synthesized by Hazra and co-workers with high yields using the CuAAC reaction promoted by microwave irradiation. Biological screening revealed that most of these conjugates possessed high antifungal activity (202 was the most active with R1 = Cl) comparable to fluconazole. However, only moderate antimicrobial potency of this library was observed (Scheme 37).145 Diverse library of bile acid-peptide conjugates joined by 1,2,3triazole, such as 204−206, was prepared by Nenajdenko et al. The required azidopeptides 207 were obtained in a multicomponent Ugi reaction using isocyanoazides as an azide source, whereas a complete set of alkyne derivatives of lithocholic, deoxycholic, and cholic acids containing one, two, or three terminal alkyne function were the products of a simple esterification or acylation by propargyloxyacetyl chloride or 4(propargyloxy)benzoyl chloride. The optimized CuAAC reaction of these components provided the corresponding conjugates 204−206 with one, two, or even three peptides attached to the steroidal core (Scheme 38). Although no application of these compounds was demonstrated, their unique structures, ranging from the linear to tweezer-like shape and diverse hydrogen bond forming pattern may be attractive for catalysis, medicinal, or supramolecular chemistry.146 Later, this approach was expanded to the preparation of analogical structures using cholesterol, mestranol, and betulinic acid.147 3.2. Steroidal Hormones and Cholesterol Modification by CuAAC
Steroidal hormones possess favorable characteristics, similar to that of bile acid in the sense of having rigid scaffold, well-defined functionality, and stereochemistry that make them valuable building blocks for construction of a diverse molecular architectures. The major difference, however, is that they have much higher lipophilicity and consequently an easy distribution in blood, passing the blood-brain barrier and skin penetration.148 More importantly, specific biological activity of steroidal hormones,44 involving the regulation of metabolism, immunological response and inflammation, ion and water balance, development of sexual characteristics and control of reproduction, to list only the most fundamental, remains attractive for development of novel or improvement of existing steroidal drugs. In this context, attention is paid on a dedicated activity, optimal pharmacokinetic profile (absorption, distribution, metabolism, and excretion ADME), or for development of a new delivery systems. A wide spectrum of biological activities of steroid hormones and related steroidal drugs prompt many research groups to modify their structure by the CuAAC reaction with the
Figure 10. Synthesis of cholaphanes 185−187 with the use of a CuAAC reaction as a ring closure step.
3.1.4. Conjugates of Bile Acids with Biologically Active Molecules. Bioconjugation of bile acids with diverse molecules toward a novel biological activity or an improvement of transport or pharmacokinetics is another large area of application of the CuAAC. Two interesting examples were reported by the group of Pore. In the first, a 1,2,4-triazole ring in the antifungal agent fluconazole was replaced by bile acid-1,2,3-triazole moiety (1,2,3triazole served as an isostere of 1,2,4-triazole). Two distinct conjugates 199 and 200 differing in the site of the bile acids attachment (C-3 and C-24 positions) were obtained by the microwave-assisted CuAAC reaction (Figure 12). Both types of these products showed high antifungal activity against Candida albicans and C. parapsilosis and Sporothrix schenckii, exhibiting a 5710
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Scheme 35. Chloride Sensor Based on Cholaphane 188 Prepared by CuAAC Macrocyclization
intention of finding compounds with new biological activity, in particular leads having anticancer potential.149 3.2.1. Steroidal Hormone Dimers, Trimers, Macrocycles, and Related Systems. A library of steroidal dimers, trimers, and tetramers was obtained by Sierra et al. starting from monovalent alkyne-mestranol 208 (an estrogen receptor agonist) and multivalent azides. The optimized CuAAC condition led to very high yields of products 209−211, ranging from 80 to 95% (Scheme 39).95 The same group showed also that the bis(alkynyl)estrone derivative 212 bearing one TMS-protected alkyne group is a convenient building block for the short synthesis of a macrocyclic dimer 213 and tricyclic molecular cage 214 using two subsequent CuAAC reactions as key steps. The route to the macrocycles involved an initial dimer 215 or trimer 216 formation followed by the TMS group removal and final cyclization. The macrocycles were prepared with good yields ca. 45% for dimers 213 and 25% for cage 214 (by assuming the formation of the very large >40-membered rings). This example clearly highlights benefits of the CuAAC reaction in macrocyclization which is competitive to widely used macrolactonization, macroaldolizations, or to the ring-closing metathesis (RCM) (Scheme 40).95 Santillan et al. reported a Fréc het−PAMAM hybrid dendrimers 217 and 218 linked by 1,2,3-triazole units as an
unimolecular micelles with an estradiol moieties as a hydrophobic core surrounded by a hydrophilic shell. The dendritic cores with 3 or 6 units of 17α-ethynylestradiol alkyne were synthesized from 1,3,5-tribromomethylbenzene. PAMAM-type dendrons of 0.5 and 1.5 generations with azide as a focal point and tert-butyl ester as end groups were selected as hydrophilic shells. The CuAAC recation of the selected dendron and the hydrophobic core alkyne group led to the products with good yields. After a coupling step, tert-butyl ester groups were hydrolyzed in trifluoroacetic acid and the corresponding dendrimers 217 and 218 with carboxylic end groups were found to be completely soluble in the phosphate buffer (Scheme 41).150 3.2.2. Steroid Modification toward New Bioactivities. Frank and Wolfling with co-workers initiated a wide project reported in a series of papers on the CuAAC modification of sex hormones of androstane and estrone series toward identification of new anticancer leads. The five androstane azides 219−223 having azido group in diverse positions of steroidal scaffold were selected, whereas estrone type moiety was represented by two azides 224−225 (Scheme 42). The CuAAC reaction of azides 219−225 with collection of mainly aryl and cycloalkyl alkynes led to the respective 1,2,3-triazole libraries 226−232. In some cases, their further diversification involved oxidation of the 5711
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Scheme 36. CuAAC Cyclization Used in the Synthesis of Secosteroidal Macrocycles with Opened Ring C 192 and Ring B 193
Figure 12. CuAAC conjugation of fluconazole analogue with bile acids.
Figure 13. Examples of bioactive steroidal 1,2,3-triazoles.
steroidal hydroxyl group to the corresponding ketones 233−235 or hydrolysis of ester 236 (Figure 13). The synthesized 1,2,3triazoles 233−236 were subjected to the screening of their cytotoxic activity against three cancer lines. A good level of in vitro antiproliferative activity was found for selected compounds. For example, 233 is selectively cytotoxic against HeLa cells, with IC50 values 1−2 μM, whereas derivatives 234−236 were found cytotoxic against HeLa, MCF-7, and A431 cells with IC50 values in the 1.7−30 μM range (Figure 13). Further experiments proved that apoptosis initiation is a possible mechanism of action of these molecules.151−154 It is worth noting that azide 219 and few activated nitriles were also used for the Cu(I)-catalyzed formation of the corresponding tetrazoles (another example of click chemistry reaction) which, in contrast to the 1,2,3-triazoles 226, were inactive toward cancer lines.154 Novel anticancer compounds based on 1,2,3-triazole-substituted pregnenolone 237 were prepared by Banday et al. by using the CuAAC reaction. A two-step synthesis starting from
Figure 11. Cyclic cholic acid−peptide conjugate 197 bearing antilysosyme CDR3 fragment and solid-supported bifunctional clickable building block 198 decorated with alkyne and azido groups.
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amination as a mixture of diastereomers. After chromatographic separation, the R diastereoisomer (configuration determined by X-ray) was used for the synthesis of ten 1,2,3-triazoles 241. Screening in vitro of the products against different parasites allowed for the identification of some compounds showing IC50 values in the low micromolar range against Leishmania donovani.156 Another interesting steroid derivative of the androstane and pregnane family 243−246 decorated by the 1,2,3-triazole ring were reported by the group of Lukashev. A series of four steroidal azides 247−250 were obtained from a glucocorticoid cortodoxone (cortexolone) 251 after the mesylation/azidation sequence, whereas epoxides 252 and 253 (pregnane-type derivatives) afforded the respective hydroxyazides 248−250 after regioselective ring opening with NaN3. Note that in the case of more sterically hindered epoxide 253 harsh reaction condition were employed to achieve the complete reaction, resulting in the formation of azide 249 as a major product of the so-called Dhomo rearrangement (and isolable minor epoxide 250). The standard CuAAC reaction carried out with azides 247−250 and a collection of ten diverse alkynes led to the expected triazoles 243−246 (Scheme 44). Contrary, a modified CuAAC reaction protocol employing copper(II) acetate and triethylamine as catalyst used for the azide 250 unexpectedly led to the rearranged triazoles 245. Use of the other modified CuAAC condition, with a triazole chelating ligand such as tris(benzyl-1,2,3-triazolyl)methylamine (TBTA) gave full conversion of the azide 250 and suppressed the unwanted D-homo rearrangement. Unfortunately, biological activity data of this rich library was not reported.157 An interesting approach to cancer therapy by using the novel radiotracer 1,2,3-triazole-linked progesterone-Tc complex 254 was reported by Banerjee et al. The idea of the use of progesterone derivatives was based on the observation that progesterone receptors are overexpressed in breast and other types of cancer and thus may serve as a potential target for a selective transportation of the suitable progesterone-linked drugs. The complex 254 was prepared by the CuAAC reaction of 11α-azidoprogesterone 255 (this position tolerates bulky substituents without reducing progesterone binding affinity) with propargyl glycine followed by coordination of [99mTc(CO)3(H2O)3]+ to the resultant triazole 256 (Scheme 45). Biological in vitro experiments revealed that 254 can bind to the progesterone receptors in MCF7 breast cancer cell lines with higher efficacy as compared to insignificant binding in nonspecific (progerestone independent) cell lines, such as HT-29. Preliminary studies on biodistribution of 254 in female Swiss mice showed favorable uptake and retention in the uterus. Nevertheless, simultaneous high uptake in blood requires further modification of 254 in order to get the desired specificity.158 Further studies reported by this group also involved the design of conceptually similar testosterone-derived radiotracer 257 dedicated to the therapy of androgen-hormon related cancers, such as prostate carcinoma. For this purpose, testosterone 258 was converted to 17α-azidoandrost-4-en-3-one 259 and allowed to react with alkyne and the technetium carbonyl complex in a one pot process to give the expected triazole product 257. Although preliminary biodistribution studies of 257 in normal male Wistar rats showed favorable uptake in prostate with significantly less uptake in other organs, unfortunately further studies revealed that the complex lost specificity against androgen receptors in in vivo experiments (Scheme 45).159
Scheme 37. Cholic and Deoxycholic Acids-β-Lactam Dimers 201 and β-Lactams-Bile Acids Conjugates 202 Linked by 1,2,3-Triazole
pregnenolone acetate 238 led to 21-bromoderivative 239, which in situ was converted into respective azide and clicked further with a series of O-propargyl phenols (Scheme 43). Screening this library against seven human cancer cell lines allowed for the identification of a few active derivatives, with triazole 237 (R = 4COMe) being the most potent one with a range of 0.03−2.78 μM.155 Pregnenolone 240 was also used by the group of Labadie for the synthesis of small collection of 1,2,3-triazoles 241 by employment of the reductive amination of the ketone group of 240, followed by the CuAAC reaction (Scheme 43). N-Propargyl amine 242, the key intermediate, was obtained after reductive 5713
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Scheme 38. CuAAC Synthesis of Diverse Bile Acid-Synthetic Peptide Conjugates
has a potent affinity to the estrogen receptor (ER) with a strong antagonistic response and a high cytotoxic activity against either MCF-7 (ER-positive) or MDA-MB-231 (ER-negative) cell lines. Unfortunately, a lack of the expected selectivity enhancement toward the estrogen receptor positive cancer cell indicated neither synergy nor cooperation within hybrid 271.161 A ribbon-type dimeric steroidal bis-triazoles 272−274 easily available from alkyne-functionalized cholic and etienic acid as well as estrone and 2,6-bis(azidomethyl)pyridine were reported by Drasar and co-workers (Figure 14). Biological screening of these products involved activation of different steroid receptors and cytotoxic assay. It was shown that triazoles 274 (X = O or NH) and 273 showed low agonistic activity on some steroidal receptors tested (ERα, ERβ, and AR), but none worked in the antagonist mode. Despite low interaction with the steroid receptors, these compounds displayed much higher cytotoxic activity. For example, 274 (X = O) acted in low micromolar concentrations against both lymphoblastic and myeloid leukemia cell lines CCRF-CEM and K562, respectively; 272 was active only in multidrug resistant cells and showed a favorable therapeutic index, whereas 273 was cytotoxic against the majority of the tested cell lines at 10 nM.162 Mestranol 208 was used by Nishimura and co-workers as one of the alkyne for the construction of a library of 1,2,3-triazoles derived from various azidosugar nucleotides designed as inhibitors of glycosyl transferases. These enzymes are important in post-translational modifications of proteins and are involved in
Another example of steroidal hormones-metal complex dyads 260−262 linked by the 1,2,3-triazole were reported by SkodaFöldes. Three different azides of the androstane type 263−265 were prepared by the opening of respective epoxides 266−268 with NaN3. The CuAAC reaction was carried out with two different ferrocene alkynes 269 and 270 as well as with other alkynes (Scheme 46). 2β- and 16β-azidoandrostanes reacted smoothly, in contrast to sterically hindered 6β-azide 265. No application of these products was reported.160 Another interesting approach to the targeting of the hormone responsive breast cancer is a hybrid 271 formed of estrone and mitomycin C linked by the 1,2,3-triazole and reported by Hanson and co-workers (Figure 14). The concept based on linking the two biologically active counterparts, one a potent estrogen receptor agonist and the second an anticancer agent. A crucial prerequisite for the success is, however, preservation of the biological activity of both linked molecules. For this reason, less synthetically accessible 11β position of estradiol has been chosen for linking as the only site not compromising of its binding with the estrogen receptor. On the other hand, alkaloid mitomycin C was selected as an anticancer drug used in the breast cancer treatment. In this case, modification of the 7-aminogroup does not diminish the alkaloid activity and thus was used for linking. The ligation of estradiole-derived azide and N7-propargyl-Nmethylmitomycin C was accomplished by the CuAAC reaction using the standard protocol. Biological tests revealed that the hybrid 271 retained the biological activity of its counterparts: it 5714
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Scheme 39. CuAAC Synthesis of Steroidal Dimers, Trimers, and Tetramers from Mestranol
decoration of mestranol 208 with a small series of dipeptides. In this case, however, the use of the catalytic amounts of CuSO4 and ascorbate in the water/DCM biphasic mixture led to a high yield of hybrids 279 (69−83%) as reported by the authors (Scheme 47).147,165 Structurally diverse library of peptide decorated steroids, including androstane 280 and 281, cholestane 282, cholane 283, and spirostane 284 type scaffolds were reported by the group of Paixão and Rivera. The CuAAC reaction of five different azidosteroids bearing the azido group either at the side chain or in the steroidal nucleus with the N-propargylamide-labeled peptides catalyzed by the Cu(OAc)2/ascorbate system enabled the preparation of the novel triazole-linked peptide−steroid conjugates 280−284 in 71−93% yields (Figure 15).166 An extension of this work involved the synthesis of the macrocyclic peptide−spirostane conjugate 285 and peptide−
many functions, such as, molecular recognition of bacterial and viral infections, cell adhesion, inflammation, or immune response, and other. By using the high-throughput quantitative MALDI-TOF MS-based screening, three potent compounds were selected, among them two with steroid moiety 275 and 276. The hybrid 275 is an inhibitor of the rat recombinant α 2,3-(N)sialyltransferase (IC50 = 8.2 μM), and 276 inhibits the human recombinant α 1,3-fucosyltransferase V (Ki = 293 nM).163 The labeling of three azido-peptides with 17α-ethinyl estradiol 277 and mestranol 208 toward novel peptidomimetics 278−279 by using the CuAAC reaction was reported by the Katritzky group. The use of azidopeptides (prone to the copper complexation) in the standard protocol (CuSO4/ascorbate) was successful but provided the resulting 1,2,3-triazoles 278a− 278d with moderate yields (Scheme 47).164 Conceptually, a similar approach was used by Nenajdenko et al. for the 5715
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Scheme 40. Synthesis of Macrocyclic Dimer 213 and Tricyclic Molecular Cage 214 Using Two Subsequent CuAAC from Estrone Derivative 212
sized by the tosylation/bromination of the protected sugars followed by substitution with NaN3 in dry DMF.167 3.2.3. Cholesterol. The covalent attachment of lipophilic cholesterol or octadecanol chain to the oligonucleotides by the CuAAC reaction as a general solution for facilitating oligonucleotide transportation across the cell membranes and enhancement of their cellular uptake was reported by Barthélémy et al. A small library of conjugates of the general formula 295 was prepared by using 5′-azido-5′-deoxythymidine and cholesterol or octadecanol propargyl ethers followed by an extension of the oligonucleotide chain via phosphoroamidites on solid support (Figure 17). The resulting conjugates were then tested for their ability to penetrate the cell, cytotoxicity, and antisense activity. The results showed that both transportation and uptake is high, in contrast to the negligible level for nonmodified oligonucleotides. In addition, these conjugates were proved to be nontoxic for the cells studied.168 Liquid-crystalline behavior of many cholesterol derivatives is often considered attractive for the construction of other mesogenic phases or preparation of special materials. Synthesis of such systems with the use of the CuAAC reaction as a linking
cholate conjugate 286, featuring different sizes and topologies depending on the used azidosteroids. Laxogenin 287 was empoloyed for the preparation of the desirable spiroazide 288, whereas 3β-azidocholic acid 289 was prepared from cholic acid. Macrocyclization was performed in the two-step protocol: initial attachment of N-propargyl decorated peptides 290 and 291 to azidosteroids 288 and 289 by amide bond formation, followed by the in situ ring closure of the intermediates 292 and 293 by the CuAAC. This reaction was carried out under the high dilution condition (1 mM) with the use of 20 mol % CuBr and led selectively to the desired products 285 and 286 with good yield (50%) and without formation of the linear and higher cyclic oligomers (Scheme 48).166 A series of ethisterone glycoconjugates 294 (Figure 16) were prepared by Tiwari et al. using the CuAAC reaction carried out at room temperature (CuI/DIPEA in DCM) or in the microwave reactor (CuSO4/ascorbate). Both protocols were found to be comparable and highly efficient, giving the products in 82−95% isolated yield, the use of microwave heating allowed, however, significant reduction of the reaction time from 12 h (rt) to 15 min. The protected azidodeoxysugars were efficiently synthe5716
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Scheme 41. Fréchet−PAMAM Hybrid Dendrimers 217 and 218 Linked by 1,2,3-Triazole
Scheme 42. CuAAC Modification of Sex Hormones of Androstane and Estrone Series toward Identification of a New Anticancer Leads
tool of dedicated cholesterol-bearing azides or alkynes has been used independently by the groups of Cui169 and Majumdar.170 Novel side chain liquid crystalline polymer 296 containing the cholesteryl moiety incorporated into poly(3-azidomethyl-3methyloxetane) polymer chain 297 was obtained by combining the ring-opening polymerization and the subsequent CuAAC reaction. For the click decoration, propargyl monocholesterylsuccinate 298 easily accessible by esterification of monocholesterylsuccinate with propargyl alcohol was chosen. The resulting polymer showed a thermotropic mesophase, as confirmed by polarized optical microscopy and differential scanning calorimetry (DSC) (Scheme 49).169 A relatively new class of liquid crystalline phases are dimesogenic (twins) or trimesogenic (triplet) compounds consisting of two or three different mesogenic units, respectively, linked by an internal spacer. Synthesis and preliminary investigation of such dimesogenic 299 and trimesogenic 300 phases containing the cholesteryl moiety as the mesogen and the
1,2,3-triazole as a linker was reported by Majumdar et al. (Figure 18).170 Zhou reported 3α-cholesteryl-(1,2,3-triazole)-PEG oligomer 301 which was prepared by the reaction of the 3α-cholesteryl 5717
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Figure 15. Peptide decorated androstane, cholestane, cholane, and spirostane conjugates prepared by CuAAC reaction.
luciferase gene transfection assay. The results demonstrated that the molecular structure of the steroid moiety and the headgroups in 302−303 are important for pDNA loading capacity, lipoplex particle size, and morphology of the resultant lipoplexes. Both cholesterol-derived lipids 302 showed much higher transfection capability than the lithocholate-derived counterparts 303.172 The CuAAC reaction of cholesterol typically use its 3αpropargyl derivatives (ethers or esters) or 3α-azide. Recent work by Woelfling et al. reported the azidation of the site at C-2 of the cholestane-type molecules by employment of a convenient twostep protocol. Thus, readily available cholestanone 308 was brominated, yielding the respective 2α-bromo-5α-cholestan-3one which underwent subsequent exchange with sodium azide to provide stereoselectively the desired 2α-azido ketone 309 (no inverted product was observed) in 84% yield. 309 Reacted with various terminal alkynes in the CuAAC reaction leading to the respective triazoles 310. Further diversification of the library was achieved by the reduction of the carbonyl group to the mixtures of epimeric 1,2,3-triazolyl alcohols 311 which can be chromatographically separated (Scheme 51). Antiproliferative screening of the 2-triazolyl-3-ketones 310 against three human cancer cell lines showed only a moderate cell-growth inhibition.173
Figure 14. Biologically active steroidal conjugates 271−276 linked by 1,2,3-triazole.
azide and propargyl-PEG by the standard CuAAC protocol (Figure 18).171 An another interesting application reported by the group of Cao et al. was a construction of cationic lipids 302 and 303 dedicated as gene carriers. These artificial hybrids were assembled by the classical CuAAC protocol using cholesterol or lithocholic acid bearing alkynes 304 or 305, respectively and two protected aminoazides 306 and 307. The hybrids combined features of cholesterol and lithocholic acid as a lipophilic counterpart and highly polar ammonium side arms (after deprotection and protonation) were selected for an interaction with nucleic acids (Scheme 50). Biological studies of 302 and 303 involved pDNA binding affinity by EB displacement and agarose-gel retardant assay as well as their cytotoxicity by MTT and LDH assay and the gene transfection efficiencies by the
3.3. Triterpenoids Modification by CuAAC
Triterpenes are widely used in medicine and in medicinal chemistry as many of them exhibit diverse biological and 5718
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Scheme 43. 1,2,3-Triazole-Substituted Pregnenolone Derivatives
Scheme 44. CuAAC Synthesis of Library of Steroidal 1,2,3-Triazoles Form Cortodoxone
3.3.1. Oleane-Type Triterpenoid Acids (Oleanolic, Betulinic, and Glycyrrethinic Acids). Oleanolic acid 312 is a pentacyclic triterpene of a broad pharmacological profile, in particular hepatoprotective and antitumor. Recently, oleanolic acid and related pentacyclic triterpenes were demonstrated to inhibit glycogen phosphorylases−enzymes involved in the
pharmacological activities, including anti-HIV, anticancer, antiinflammatory, and antihepatits properties.174−178 Some triterpenoids, such as oleanolic, ursolic, maslinic, betulinic, and glycyrrethinic acids, are also highly abundant in plants and are therefore available in large quantities that make them an especially attractive scaffold for further modification, also by using the CuAAC reaction. 5719
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Scheme 45. CuAAC Synthesis of Progesterone-Tc Complex Radiotracer 254 and Testosterone-Derived Radiotracer 257
Scheme 46. Steroidal Hormones-Ferrocene Dyads 260−262 Linked by the 1,2,3-Triazole
metabolism of glycogen, thus being potentially a target for diabetes therapy. Studies on the development of new inhibitors of glycogen phosphorylases based on oleanolic acid-sugar conjugates prepared by the CuAAC reaction were conducted by two independent groups of Xie and Sum and Somsak. The idea is based on the design of the conjugate where oleanolic acid binds to the enzyme at the allosteric site, whereas the glucose analogue will access the catalytic site serving as an inhibitor. The covalent linking of the oleanolic acid with sugar by the proper linker based on 1,2,3-triazole (or other type) may thus lead to a doubling of the interaction with the enzyme, giving more potent heterobivalent inhibitors. The first attempt to this goal reported by Xie and co-workers involved a synthesis of oleanolic acid glucoconjugates 313−315. Oleanoic acid 312 was easily
transformed into two respective alkynes 316 and 317 at the C28 and C-3 position, respectively, whereas azide 318 was prepared by using the 28-carboxylic group. The synthesis of 1,2,3-triazole conjugates 313−315 was efficiently performed by using the CuAAC reaction with standard protocol (Scheme 52). Enzymatic assays of these products showed that conjugates 313− 315 exhibited moderate-to-good inhibitory activity against rabbit muscle glycogen phosphorylase, and compound 313 was identified as the most potent inhibitor, with an IC50 value of 1.14 μM (note that the parent oleanolic acid has IC50 = 14 μM).179 A similar approach was reported by Sum and Somsák who prepared a large library of glycoconjugates 319 and 320 of three triterpenoid acids: oleanolic 312, ursolic, and maslinic. The acids were converted into respective propargyl esters and subjected to 5720
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Scheme 47. CuAAC Synthesis of Estradiol and MestranolPeptide Conjugates 278−279
Figure 16. CuAAC synthesis of ethisterone glycoconjugates.
Figure 17. Cholesterol-based oligonucleotide transporter.
the CuAAC reaction with the five-protected D-glucose azide derivatives differing in the linker length. After deprotection of the sugar moiety, all of the conjugates were assayed against two rabbit muscle glycogen phosphorylases. The inhibitory potency did not exceed those of the parent triterpenoic acids (typically, best results were obtained for oleanoic acid conjugates), and only some of the conjugates 319−320 showed a modest activity (IC50 26−70 μM, Figure 19).180 A further expansion of this study conducted by Xie involved a synthesis of homodimers of oleanolic acid linked by 1,2,3triazole, amide, and ester linkage. The CuAAC reaction was found to be superior in the library preparation, giving nearly a quantitative yield of products. Their biological evaluation against rabbit muscle glycogen phosphorylase allowed for the identification of two potent inhibitors, among them one with the 1,2,3triazole linkage 321 which showed an IC50 value of ca. 3 μM (Figure 19).181 A series of conceptually similar oleanane-type glycoconjugates 322 and dimers 323 were prepared by the group of Zhou as novel HCV inhibitor candidates. An initial screening revealed that
Figure 18. CuAAC synthesis of cholesterol-derived dimesogenic 299 and trimesogenic 300 phases and 3α-cholesteryl-(1,2,3-triazole)-PEG oligomer 301.
oleanolic acid 312 had weak potency to inhibit HCV (IC50 of 10 μM), but its analogue α-hydroxylated at C-16 (echinocystic acid 324) is a much more active lead (IC50 at 1.4 μM). This triterpene was thus selected as a pharmcophore and transformed into the clickable N-propargylamide 325 for further conjugation with a series of azidosugars or diazides by using the standard CuAAC protocol (Scheme 53). The triazole-linked glycoconjugates 322 were moderately active, in contrast to the ester-linked counterparts, but dimeric triterpene 323 linked by the 1,2,3-triazole was 5721
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anticancer, thus is a good platform for developing new bioactive leads.186−188 An interesting library of 1,2,3-triazole linked conjugates 332 and 333 of betulin and betulinic acid, respectively, with AZT (26, 3′-azido-3′-deoxythymidine) was reported by Bori and coworkers as a part of a screening project toward novel anti-HIV agents. Betulin 330 and betulinic acid 331 were easily decorated by the propargyl group at the C-3 and C-28 positions, providing the key alkynes 334 and 335 which underwent the CuAAC reaction with AZT. An anti-HIV assay in vitro showed that conjugates 332 linked through the C-3 position of betulin or betulinic acid have moderate antiviral activity (EC50 = 0.19 and 0.35 μM, respectively). Much better results, however, were obtained for both alkyne 335 equipped with a 3-O-3,3dimethylsuccinyl substituent at C-3 and the propynyl ester at C-28 (analogue of anti-HIV bevirimat) and its AZT-conjugate 333. Products 332 and 333 showed high anti-HIV activity with an EC50 of 0.067 and 0.10 μM (comparable to that of AZT) and a very good selectivity index (ratio of cytotoxic/antiviral activity) of 226 and 101, respectively (Scheme 56).189 A more sophisticated approach in the development of novel anti-HIV agents based on the triterpenoic acid pharmacophores was demonstated by Jiang, Liu, and co-workers. The idea was to link nonspecific antiviral triterpenes such as betulinic 331, oleanolic 312, or ursolic acid with T20 peptide (enfuvirtide), which contains a helix zone-binding domain (HBD) and is a gp41-specific HIV-1 fusion inhibitor. As a linking method, the CuAAC reaction was selected with the use of a large library of the alkyne-bearing triterpenoic acids, for example 336 and 337 and the azide-modified HBD-containing peptides 338 and 339, either in solution or in a solid-phase format (Scheme 57). The resultant conjugates 340 and 341 showed a strong cooperative effect against HIV-1 Env-mediated cell−cell fusion, in contrast to the unbound counterparts which showed only weak activity. Among them, products 341 exhibited high anti-HIV-1 activity against both the T20-sensitive and -resistant HIV-1 strains with EC50 of 3.3−3.9 nM for the most active leads and improved pharmacokinetic properties.190 A library of betulinic acid substituted at C-3 with the 1,2,3triazole moiety was prepared by Koul et al. The two-step synthesis involved initial O-propargylation of the 3β-hydroxyl group of the betulinic acid 331 leading to alkyne 342 followed by the CuAAC reaction with a series of the aryl and sugar azides (Scheme 58). The products 343 were obtained in high yield and tested for their cytotoxic activity against nine human cancer cell lines. Most of the triazoles 343 showed higher cytotoxicity as compared to the parent betulinic acid. Among them, two compounds 343 bearing the 2-cyanophenyl and 5-hydroxynaphth-1-yl substituent displayed low μM IC50 values, for example, IC50 2.5 and 3.5 μM against the leukemia cell line HL60, respectively (5−7-fold higher than betulinic acid).191 The modification of lupane triterpenoids is typically carried out at the C-3 hydroxyl or C-28 carboxylic group. Recently, Shul’ts and co-workers demonstrated an interesting route to the lupanes decorated with the azido group at C-30. The isopropenyl group of the triterpene was initially reacted with NBS, yielding respective allyl bromide followed by the nuclophilic substitution with sodium azide in acetonitrile. Lupane azides 344 were then subjected to the CuAAC reaction with a few alkynes giving the respective triazoles 345 in good yield (Scheme 59). The Ames test carried out for the obtained product showed no mutagenicity thereof.192
Figure 19. Oleanolic, ursolic, and maslinic acid glycoconjugates 319− 320 and 1,2,3-triazole-linked homodimer of oleanolic acid 321.
found to be the most active leads with IC50 at ∼10 nM.182 Optimization of this structure by varying the length, rigidity, and hydrophobicity of the linker resulted in the identification of the additional few very potent inhibititors, with IC50 values extending into the nanomolar level.183 Oleanolic alkynyl esters 326 were employed by the group of Pertino for the synthesis of 18 new triazoles 327 by using a series of aryl azides. The substrates and products were screened toward their antiproliferative activity by using normal lung fibroblasts (MRC-5) and four cancer cell lines. Among the triazoles 327, remarkable activity was found for the product with pchlorophenyl group which showed selective effect against adenocarcinoma AGS cells with an IC50 value of 8.9 μM and with the p-toluenesulphonyl group with IC50 11.5−22.2 μM (Scheme 54).184 Oleanolic acid 312 was also used by Hu et al. for a synthesis of the macrocyclic dimer 328 designed as an anion receptor. Cyclization of the bifunctional derivative 329 obtained in three steps from oleanloic acid was carried out by the CuAAC reaction and led to the desired product with 25% yield. Macrocycle 328 exhibited selectivity and affinity of binding of the fluoride ion through C−H···F hydrogen bond interactions (Scheme 55).185 Betulin 330 and betulinic acid 331 is another example of the pentacyclic triterpenoid occurring in many plants, mainly in the bark of white birch (Betula pubescens). Betulin has a broad spectrum of biological activities, including antiretroviral, antimalarial, and anti-inflammatory as well as recently reported 5722
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Scheme 48. Macrocyclic Peptide−Spirostane 285 and Peptide−Cholate 286 by CuAAC-Triggered Macrocyclization
glycoside, glycyrrhizin isolated from the liquorice roots of Glycyrrhiza glabra. This chiral polyfunctional scaffold was used by Ju and co-workers for the construction of a series of tweezers 352 and macrocyclic or C3-symmetrical receptors 353 and 354, respectively. All these compounds were prepared with the aid of the CuAAC reaction from the properly azide- or alkyne-derived glycyrrhetinic acid. Some of these products exhibited interesting properties, such as the trimeric 354 which could self-assemble into nanoscale fibers,195 or 352 which selectively coordinated Hg2+ cations.196 On the other hand, the glycyrrhetinic acid based macrocycle 353 showed remarkable selectivity and affinity for both F− and Hg2+ ions. In this dual-responsive molecular recognition process, roles of either 1,2,3-triazole ring, the carbonyl group, and the triterpenoid rigid skeleton was evidenced (Scheme 61).197 Glycyrrhetinic acid 351 modification by the CuAAC reaction was also used in medicinal chemistry. For example, Misra et al. reported an interesting library of the glycyrrhetinic acid-sugar dyads 355 and triads 356 linked by 1,2,3-triazole. Propargylation of 351 led to the mono- and bis-propargylated derivatives 357 and 358 in 69% and 15% yield, respectively. After separation, both alkyne-functionalized products were efficiently reacted with
Betulonic acid 346 (keto group at C-3) was used for the synthesis of a small series of 1,2,3-triazoles 347 by Alabugin and co-workers. The key-alkyne component derived from 346 was the alkynyl amide 348 which underwent the CuAAC reaction with four simple aliphatic and aromatic azides. The prepared compounds were analyzed by PASS software (Prediction Activity Spectra of Substances), and on this basis their predicted antiinflammatory and antioxidant activity has been verified experimentally. Unfortunately, low anti-inflammatory activity was demonstrated using histamine-induced paw edema model, in contrast to CCl4-induced hepatitis, where amide 348 with aryl substituents showed slightly better activity as compared with the reference antioxidant−dihydroquercetin (Scheme 60).194 Betulonic acid 346 was also used by the group of Nenajdenko et al. for the preparation of few conjugates 349 with unnatural synthetic dipeptides. Betulonic acid propargyl ester 350 was reacted with the azidopeptides by employing the standard CuAAC protocol giving the desired products 349 with moderate to good yields (Scheme 60). The conjugates showed to be inactive in an anti-inflammatory screening test.193 Glycyrrhetinic acid 351 is another bioactive pentacyclic triterpenoid obtained, for example, by the hydrolysis of its 5723
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Scheme 49. Liquid Crystalline Polymer 296 Containing Cholesteryl Moiety Incorporated into Poly(3-azidomethyl-3methyloxetane) Polymer 297 by Combined Ring-Opening Polymerization and CuAAC Reaction
Scheme 51. Access to C-2 1,2,3-Triazolyl-Substituted Cholestanes 311
human cell expressing β2AR. The first approach was based on the click reaction of azide-functionalized glycerrhetinic acid 359 and alkyne-derived fluorophores −4-ethynyl-N-ethyl-1,8-naphthalimide 360199 or the CdTe/ZnS quantum dot 361.200 Both reacting systems were able to react in the presence of Cu(I) to give the respective triazole-linked conjugates giving fluorescent emission at 465 or 620 nm, respectively, and detect 351 target located in the HEK293-β2AR cell membranes (Figure 20). 3.3.2. Triterpene Saponins. Steroidal saponins are widely distributed among the plant kingdom and are important drugs used in traditional medicine.201 Currently, several compounds of this class were demonstrated to show a potent cytotoxic, antifungal, anti-inflammatory, and antiviral activities, thus the saponins continue to be attractive for medicinal chemistry. Among steroidal saponins, the most abundant are those containing a spirostanic aglycone and the oligosaccharide moiety directly attached to the C-3 hydroxyl group. Such spirostanic steroids were used by Rivera et al. for the synthesis of the library of saponins-oligosaccharide hybrids 362−364 by the CuAAC
a series of peracetylated sugar azides using CuSO4 and D-glucose as the copper reducing agent (Scheme 62). The synthesized triazoles 355 and 356 as well as their counterparts with the free hydroxyl groups in sugars were evaluated for their anticancer activity against human cervical cancer cells (HeLa) and normal kidney epithelial (NKE) cells. None of the compounds exceeded the activity of the parent glycyrrhetinic acid.198 Glycerrhetinic acid 351 has also synergistic antiasthmatic effects with the β2-adrenergic receptor (β2AR) agonist via the β2AR-mediated pathway. The group of Ge has developed a specific assay for the fluorescent visualization of 351 in the
Scheme 50. CuAAC Synthesis of Cholesterol or Lithocholic Acid Based Cationic Lipids 302 and 303 Dedicated As a Gene Carriers
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Scheme 52. CuAAC Synthesis of Oleanolic Acid Glucoconjugates
Scheme 53. Echinocystic Acid Glycoconjugates and Dimers Linked by 1,2,3-Triazole
Scheme 54. CuAAC Synthesis of Oleanolic Acid 1,2,3Triazoles 327
reaction bearing a 1,2,3-triazole ring as a surrogate of the glycosidic linkage. For this purpose, a series of the alkyne and azido-functionalized spirostanic building blocks 365−367 keeping structural resemblance to the aglycones of the most cytotoxic saponins and having diverse functionalization patterns on rings B and C were prepared from diosgenin 368, hecogenin 369, and 5hydroxylaxogenin 370. These substrates were reacted with a large library of the properly functionalized trisaccharides.
Unfortunately, despite logic assumptions, none of the synthesized conjugates 362−364 exhibited significant cytotoxic activity.202 Continuation of this project involved also a synthesis of the new dimeric spirostanic steroids 371 linked by the 1,2,3triazole ring. Biological data regarding their activity were not reported (Scheme 63).203 The preparation of similar 1,2,3triazole linked glycoconjugates of diosgenin, cholesterol, and bile acids having one, two, or three sugar units was also reported by the Deobald group.204 The horse chestnut saponin mixture known as escin is another widly abundant saponin used as an active pharmaceutical ingredient in many preparations. Escin is a convenient source of protoescigenin 372its major source is triterpene aglycone. 5725
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employed in medicial chemistry or in agrochemistry as plant hormones and pheromones. They are also used for pest control as colorants for food and cosmetics. Last but not least many essential oils and their constituets are crucial in perfumery and modern fragrance industry.206 Although their biosynthesis operates by rather conceptually simple modular condensation of the isopentenyl and dimethylallyl pyrophosphate, carbocation cascades of the linear biosynthetic intermediates catalyzed by specific cyclases led to an enormous structural diversity in mono, bi-, tri-, and polycyclic products. They typically undergo further stereoselective functionalization providing more polar products which can additionally be modified. Interestingly, despite a wide occurrence and availability of these groups of isoprenoids, they are so far much less frequently used as a substrates in the CuAAC reaction. 3.4.1. Mono- and Sesquiterpenes. Geraniol and farnesol were selected by Blache et al. as a scaffold for preparation of novel bacterial antibiofilm compounds 376 and 377, which mimic naturally occurring highly active isoprenoids such as geranylgeranyltoluquinol 378 or cinnamic acid derivative 379. In the first attempt, geranyl and farnezyl azides and alkynes were selected as partners for the CuAAC reaction. Unfortunately, azidation of the terpenoid (allylic) bromides 380 and 381 was accompanied by a substantial isomerization giving a mixture of difficult to separate Z and E isomeric azides, which consequently provided the corresponding mixture of 1,2,3-triazoles 376 (Scheme 65). The isomerization of allylic azides resulted from their facile [3,3]sigmatropic rearrangement, results in an equilibrium of the primary and tertiary azides and generally complicate the synthesis of such type 1,2,3-triazoles (for more detailed discussion see ref 207). Later, this strategy was reversed by the use of the propargyl ethers of terpenoid alcohols 382 and 383 and a series of aromatic azides (Scheme 65). Biological tests for the inhibition of the biofilm formation of Pseudoalteromonas sp. D41 with the use of E/Z-mixture of 376 allowed for the selection of two active leads, with pmethoxyphenyl and 3,5-dimethoxyphenyl as substituents.208 Similar screening performed for the second library 384 and 385,
Scheme 55. Oleanolic Acid Macrocyclic Dimer 328 Designed As an Anion Receptor
This compound was used for the synthesis of glycoconjugates 373 with the aid of the CuAAC reaction by the group of Grynkiewicz. The isopropylidene protection followed by Opropargylation of polyhydroxylated substrate 372 led to two major propargyl ethers 374 and 375. Alkyne 374 reacted with a series of azido-O-protected monosaccharides in the CuAAC reaction providing access to the protoescigenin 1,2,3-triazolelinked glycoconjugates 373 (Scheme 64). No biological data of these products were reported.205 3.4. Other Isoprenoids Modification by CuAAC
Mono-, sesqui, di-, and polyprenoids constitute a very rich class of natural products with many bioactive compounds widely
Scheme 56. CuAAC Synthesis of Betulin and Betulinic Acid-AZT Conjugates
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Scheme 57. CuAAC Conjugation of Triterpenoic Acids with T20 Peptide (Enfuvirtide) Toward Novel Anti-HIV Agents
Scheme 58. CuAAC Synthesis of Betulinic Acid Substituted at C-3 with 1,2,3-Triazoles
Scheme 59. Route to Lupanes Decorated with Azido Group at C-30 and Their Subsequent CuAAC Reaction
showed that the most active is a geranyl-derived triazole 384 bearing the m-carboxyphenyl group.209 Protein prenylation is an important hydrophobic posttranslational enzymatic modification covalently attaching an isoprenoid chain to the protein by specific prenyltransferases. These enzymes utilize farnesyl or geranylgeranyl diphosphate as substrates and are widely distributed in living organisms as the prenylation of numerous proteins involves approximately 2% of all mammalian proteins. Importantly, the prenylation includes also some types of the proteins of the Ras superfamily, and there is strong evidence that the K-Ras proteins are involved in approximately 20−30% of all human cancers. For this reason, the development of the prenyltransferase inhibitors is an important
goal for design of novel anticancer drugs as well as tracing of the prenylation dynamics and its protein targets in living organisms.210 Wiemer et al. used geranyl 386, farnesyl 387, and geranylogeranyl 388 azides for the preparation of a small set of triazole bisphosphonates 389 dedicated as novel inhibitors of geranylgeranyltransferase II (GGTase II). These compounds were designed to mimic natural substrates by assembling the nonpolar isoprenyl chain with the polar bisphosphonate headgroup used as the diphosphate surrogate. The synthesis of 389 was based on the CuAAC reaction of alkyne-functionalized bisphosphonate 390 with a series of prenyl azides 386−388 under standard conditions, followed by hydrolysis of resulting 5727
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Scheme 60. CuAAC Synthesis of Betulonic Acid 1,2,3-Triazoles
Scheme 61. Glycyrrhetinic Acid Tweezers 352 and Macrocyclic and C3-Symmetrical Receptors 353 and 354 Prepared by CuAAC
moderate active lead (IC50 0.1 mM), whereas their cytotoxicity studied in the human myeloma RPMI-8226 cell line showed them to be weak and did not correlate with the GGTase II inhibitory activity.211 The same group demonstrated later a stereoselective variant of this synthesis by using geranyl and neryl epoxyazides for the CuAAC reaction followed by regeneration of the olefin
1,2,3-triazole bisphohonates 389 to the corresponding bisphosphoric acid sodium salts (Scheme 66). As mentioned before, substantial isomerization of prenyl azides was again observed, favoring the formation of the 2:1 mixture of the Eisomer for geranyl azide 386 (judged from 1H NMR spectra). Screening of 389 against the inhibition of GGTase II allowed for identification of the triazole bearing a geranylgeranyl chain as the 5728
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assay, and surprisingly, neryl triazole 396 was found to be the most potent inhibitor with an IC50 of 375 nM.212 Farnesyl analogues 397 with the 1,2,3-triazole moiety replacing internal isoprene unit, dedicated as another inhibitor of protein prenylation were reported by Spielmann et al. These compounds mimic the farnesyl pyrophosphate 398, which is a natural substrate for the protein prenylation by dedicated farnesyltransferases. Structure of 397 was greatly simplified as compared to 398, since the terminal isoprene unit was replaced by the benzyl moiety, whereas the internal isoprene part was substituted by the 1,2,3-triazole ring. The mimic 397 was prepared by solid-phase methodology, with the use of resinimmobilized alkyne alcohol 399 and in situ generated benzyl azides followed by the CuAAC reaction catalyzed by CuI/ DIPEA. Unfortunatelly, no data regarding biological activity of these products were given (Scheme 67).213 Another enzyme involved in the prenylation of proteins and being a promising target for medicinal chemistry is isoprenylcysteine carboxyl methyltransferase (Icmt) catalyzing esterification of carboxylic group of prenylcysteine by using S-adenosylmethionine as the methyl donor. Gibbs and co-workers used the CuAAC reaction for assembling the Icmt inhibitor based on the motif of farnesyl thiopropionic acid 400, known as the Icmt inhibitor. Initially, a library of the mimics 401 was designed, in which the allylic thioeter part of 400 was replaced by the 1,2,3triazole but both the prenyl chain and carboxylic group remained. As these products were shown to be weak inhibitors of Icmt, further SAR studies greatly simplified the triazole structures, eventually leading to the highly active candidate 402 containing the biphenyl substituent instead of the prenyl moiety (IC50 = 0.8 ± 0.1 μM; calculated Ki = 0.4 μM) (Figure 21).214 The identification and quantification of proteins both in vivo or in vitro is of primary importance for current life sciences, and the CuAAC reaction potential was early recognized in this field.215 Typically, the CuAAC reaction is used for the preparation of fluorescent probes or labeling and visualization of the suitable modified alkynes or azides incorporated into desired biomolecules. A new approach to both labeling and quantifying of the prenylated proteins was reported by the groups of Tamanoi and Distefano. Tamanoi used a commercially available (click-iT) azido-functionalized geranylgeraniol 403 which incubated with cells that underwent metabolic incorporation. After cell lysis, prenylated proteins were conjugated with fluorescent tetramethylrodamine alkyne 404a by using the CuAAC reaction. The labeled proteins were then separated by both one- and twodimensional (1D and 2D, respectively) electrophoresis and detected with fluorescence imaging. Alternatively, LC−MS/MS analysis can also be used for the detection of geranylgeranylated proteins.216 Distefano and co-workers demonstrated in broader studies that both the azide- or alkyne-functionalized geraniol 405 and 406 and farnesol 407 derivatives (for their synthesis see refs 217 and 218) readily penetrate the mammalian cells in a culture and become incorporated into proteins that are normally prenylated. Similarly, after the cell lyses, the labeling of prenylated proteins was carried out by the CuAAC reaction with the use of an excess of fluorescent azido- or propargyl-functionalized tetramethylcarboxyrhodamine (404a−404b). 2D Electrophoretic separation followed by the MS analysis allowed identification of the labeled proteins.219 A similar bioorthogonal approach employing the CuAAC reaction of protein-incorporated farnesyl analogue 407 with azidorhodamine 404b as a tag was also used by Hang for the
Scheme 62. Glycyrrhetinic Acid-Sugar Dyads 355 and Triads 356 Linked by 1,2,3-Triazole
Figure 20. Azide-functionalized glycerrhetinic acid 359 and alkyne fluorophores −4-ethynyl-N-ethyl-1,8-naphthalimide 360 and CdTe/ ZnS quantum dot 361 for fluorescent visualization of glycerrhetinic acid.
functionality (Scheme 66). Epoxyazides 391 and 392 were employed as protected olefins to hamper sigmatropic rearrangement of allylic azides. These substrates were prepared by the regioselective epoxidation of geraniol or nerol followed by a mesylation/bromination sequence with the final azide substitution (no epoxide opening was reported). Epoxyazides 391 and 392 were immediately used for the CuAAC reaction with alkyne 390 affording the corresponding triazoles 393 and 394. In the next step, 393 and 394 were selectively transformed into Eor Z-olefins, respectively, by using NaI and trifluoroacetic anhydride followed by hydrolysis of the phosphonate to provide the desired sodium salts 395 and 396 (Scheme 66). All products were tested in an in vitro GGDPS enzyme inhibition and cellular 5729
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Scheme 63. CuAAC Synthesis of Saponins-Oligosaccharide Hybrids 362−364 and Spirostanic Steroid Dimers 371
antiviral agent. 416 Was used by Dong, Aisa, et al. for the preparation of a library of 1,2,3-triazole derivatives 417 as a novel antiviral leads against influenza. The carboxylic group of 416 was converted into propagyl ester 418 and N-propargyl amide 419, which subsequently underwent the CuAAC reaction with a series of benzyl or cyclohexane derived azides (Scheme 69). Among these products, nine compounds were identified to be active against the H1N1 strain of influenza A virus with the most active being 417a (of comparable activity to the reference drugs, Oseltamivir and Ribavirin). Some of them were also active on the Oseltamivir resistant H1N1 strain. Most of the products were also active against influenza B virus, and seven members of the libray 417b−417e exhibited higher activity as compared to Ribavirin. Four best compounds were also evaluated in a plaque assay experiment using MDCK cells and RBV as a control compound and three derivatives 417b and 417d were found to be more active than RBV in inhibiting plaque formation.224 3.4.2. Sesquiterpene Lactones. Sesquiterpene lactones are a large group of over 5000 known compounds built from three isoprene units and containing a lactone ring which are widely distributed among the plant kingdom, being common in many families, in Asteraceae, in particular.225,226 These secondary metabolites possess a broad spectrum of biological activities such as, anticancer, antibacterial, and antiinflammatory among others, thus are an important field of the exploration in medicinal chemistry. Ludartin 420 and parthenin 421 guaiane-type sesquiterpene lactones exhibit anticancer activity, and thus were used as pharmacophores for furher derivatization and SAR studies. 420
development of an improved protocol of prenylome profiling (Figure 22).220 Distefano reported also a prenylated polypeptide 408 bearing alkyne function for studying the cellular transport.221 The CuAAC was also used by Zhao for the preparation of a photoaffinity probe 409 containing both isoprenoid chain and biotin tags (Figure 22).222 The Distefano group demonstrated recently an interesting triorthogonal reagent 410 designed for a dual protein labeling. This molecule contains the prenyl pyrophosphate chain that allows its enzymatic incorporation in a living cell into proteins containing a C-terminal CaaX-box amino acid sequence, such as 411 by using prenyl trasferases. Such labeled protein 412 thanks to the presence of both alkyne and aldehyde functionality can further be site-specifically decorated by external molecules such as other protein, low molecular weight tags, fluorophore, or polyethylene glycol leading to the respective triazoles 413 or oximes 414. Demonstration of the capability of reagent 410 was performed on two proteins, namely, green fluorescent protein (GFP) and therapeutically useful ciliary neurotrophic factor (CNTF). In the first step, both proteins were enzymatically modified with the compound 410 followed by the simultaneous oxime and CuAAC ligation reaction to incorporate azidotetramethylrhodamine and aminoxydansyl fluorophores in the modified protein 415 or an aminooxy-PEG (Scheme 68).223 Rupestonic acid 416, a guaiane type sesquiterpene was isolated from Artemisia rupestris L, a well-known chinese medicinal plant traditionally used for detoxification, antihypersusceptibility, and for protecting the liver. It is also a antitumor, antibacterial, and 5730
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Scheme 64. CuAAC Synthesis of Protoescigenin Glycoconjugates 373
Scheme 65. 1,2,3-Triazole Derivatives of Geraniol and Farnezol Designed As Bacterial Anti-Biofilm Drugs
was used by Bhat et al. for the synthesis of derivatives 422 with a 1,2,3-triazole ring mounted at the C-11 postion in the sesquiterpenoid moiety. Two-step synthesis involved an initial Michael addition of the propargyl amine to the highly reactive αmethylene-γ-lactone motif of 420 (with creation of the new Rconfigurated chiral center at C-11) followed by the CuAAC reaction of N-propargyl amine 423 with a series of aromatic azides (Scheme 70). These products were screened against five human cancer cell lines, but none of them exceeded the activity of the parent ludartin.227 Better results were reported by the group of Kumar who prepared a library of 1,2,3-triazole-substituted structurally related coronopilin 424 (1,2-dihydroparthenin). Parthenin 421 itself is a highy bioactive (anticancer, antibacterial, antiamoebic, and antiinflammatory) sesquiterpene lactone occurring as a major constituent of the herb Parthenium hysterophorus L. that grows wild in India. Regio- and stereoselective Micheal addition of trimethylsilylazide to the cyclopentonone ring of parthenin yields efficiently the respective azide 425 used further in the CuAAC reaction with a number of propargyl ethers, propargyl amines, or terminal acetylenes (Scheme 70). The prepared
triazoles 424 were subjected to the cytotoxicity screening against a panel of six human cancer cell lines PC-3, THP-1, HCT-15, HeLa, A-549, and MCF-7, and one compound 424 (R = 2ClC6H5) showed a good cytotoxic potency at low micromolar IC50 values.228 3.4.3. Diterpenoids. Diterpenoids constitute a large group of isoprenoids with more than 12000 compounds originating from 20 carbon atoms precursor, geranylgeraniol pyrophosphate. Its enzymatic transformation leads to the asthonising molecular diversity and function. Beside natural biological action of diterpenoids in plants such as, hormones or defense systems, their representatives possess also anticancer, antimicrobial, antifungal, analgesic, flavouring, and psychoactive properties.229 Resin acids 426 including abietic, dehydroabietic, and many other tricyclic diterpenoic acids are isolated on the industrial scale from resins mainly of genus Pinus. These raw renewable acids are valuable materials for the preparation of polymers.230,231 Propargyl esters of such raw materials (predominately containing propargyl abietylate 427) were used by Tang and co-workers for the synthesis of a biodegradable graft copolymers in a combination of the ROMP/CuAAC strategy. Propargyl esters of raw resin acids were attached to the azidofunctionalized polycaprolactone 428 via the CuACC reaction giving degradable highly hydrophobic polymer 429 showing a contact angle similar to that of polystyrene (80−90 °C) and low water uptake (Scheme 71).232 Dehydroabietic acid 430 was used by the group of Pertino et al. as a bioactive scaffold for the preparation of 16-members library of triazoles 431 and 432 by using the standard CuAAC reaction protocol. 430 And the product of its reduction dehydroabietinol 433 were esterified by alkyne alcohols or acids, respectively, giving the desired alkynes 434 and 435. The CuAAC reaction 5731
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Scheme 66. Access to Linear Terpenoid 1,2,3-Triazole Bisphosphonates 389 and 395−396 as Novel Inhibitors of Geranylgeranyltransferase II
Scheme 67. Farnesyl Pyrophosphate Mimic 397 with Internal and Terminal Isoprene Units Replaced by 1,2,3-Triazole and Benzyl, Respectively
Figure 21. Farnesyl thiopropionic acid 400 1,2,3-triazole mimics 401− 402 as inhibitors of protein prenylation.
highly active candidates, with the best compound having IC50 of 6.1 μM for lung cancer (SK-MES-1 line).233 Diterpenoid-type antibiotic pleuromutilin 436 has a modest antibacterial activity and works by the inhibition of the bacterial protein synthesis by binding to the ribosomes. It was shown that the modification of the C-14 position of 436 increases its activity and some semisynthetic compounds, such as retapamulin, were
carried out with series of aryl and benzyl azides led the triazoles 431 and 432 in good yields (Scheme 72). Antiproliferative screening of these products against a few human cell lines gave no 5732
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Scheme 68. Triorthogonal Reagent 410 Designed for a Dual Protein Labeling
Scheme 69. CuAAC Synthesis of Rupestonic Acid Library of 1,2,3-Triazole Derivatives
Figure 22. Reagents for labeling and detection of protein prenylation by CuAAC reaction and miscellaneous terpenoid probes.
approved for human treatment. Modification of 436 by employing the CuAAC reaction was reported in a series of papers by Nielsen, Vester, et al. In the first step, a library of 19 novel pleuromutilin conjugates with different nucleoside bases as side chain extensions were synthesized for SAR studies. Specifically, 436 was easily derivatized at position C-22 into the corresponding azide 437 and reacted with a series of alkynefunctionalized nucleobases or nucleosides under the standard CuAAC condition (Scheme 73). The binding assay of the resultant products 438 by using chemical footprinting of nucleotide U2506 in 23S rRNA allowed for the identification of triazole 438a containing the adenine-9-yl moiety with the
propyl linker as one with the highest affinity and of significantly higher binding than pleuromutilin itself.234 5733
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Scheme 70. CuAAC Synthesis of Ludartin and Parthenin 1,2,3-Triazoles Mounted at C-11
Scheme 72. CuAAC Synthesis of Dehydroabietic Acid Triazoles 431 and 432
Scheme 73. CuAAC Synthesis of Pleuromutilin Antibacterial Conjugates
Scheme 71. Resin Acid Biodegradable Graft Copolymers 429 Prepared by Combination of ROMP/CuAAC Reaction
specific PTC site in the ribosome better than the parent pleuromutilin X. Among them, conjugate 438d showed the highest binding affinity comparable to that of the known drugs valnemulin and tiamulin and exhibited also good inhibitory potency (MIC) against few bacterial strains.235,236 Recent, more extensive optimization studies on these candidates confirmed the highest potency of 438d but allowed for the identification of three other conjugates 438b−438c and 438d, which in tests on two Staphylococcus aureus strains showed activity comparable to that of tiamulin and valnemulin (Scheme 73).236 Naturally occurring labdane class imbricatolic acid 439 was employed by Pertino for the synthesis of a series of triazoles 440 and triazole-linked dimers 441. Their preparation started from the readily available azide 442 obtained by the tosylation/azide exchange of the side chain hydroxyl group (Scheme 74) or alkyne
Further studies involved an optimization of the linker binding nucleobase with the 1,2,3-triazole ring. Seven of eleven novel conjugates 438b−438f in this series equipped with a conformationally restricted or isosteric linkers were found to bind to the 5734
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Scheme 74. CuAAC Synthesis of Imbricatolic and Grindelic Acid Derived 1,2,3-Triazoles and Dimers
443. Screening of these products showed their weak antiproliferative activity.237 Garcia and Donadel et al. used another labdane-type diterpenoid grindelic acid 444 as a scaffold for the preparation of a library of derivatives dedicated as anticancer leads. Among various syntheses considered, the CuAAC reaction was also selected for the transformation of 444 into the corresponding triazoles 445 and triazole-linked dimers 446. Specifically, 444 was converted into side chain modified azide 447, terminal acetylene 448 and N-propargylcarbamate 449. In the next step, azide 447 was used for the synthesis of a small collection of triazoles 445 using mono- and diacetylenes under the standard CuAAC protocol (Scheme 74). Although none of these triazoles showed high cytotoxic activity, most of them were significantly more active than parent diterpene 444.238 Comprehensive synthetic work on the regio- and stereoselective azidaton of oridonin 450 was reported by the group of Zhou. This highly oxygenated and functionalized 7,20-epoxy-entkaurane-type diterpenoid is isolated from the traditional Chinese herb Isodon rubescens and shows promising anticancer activity. A quest for more active, soluble, and bioavailable analogues of oridonin requires the development of its reliable and stereoselective transformations. Azidation of 450 proved to be a valuable tool for the diversification of that diterpene, allowing selective installation of the azido group in positions C-1, C-2, and C-3 of ring A. All three azides 451−453 were demonstrated to efficiently react with model phenyl- and 4-tert-butylphenylacetylene in the CuAAC reaction using CuI as a catalyst, yielding respective 1,2,3-triazoles 454−456 (Scheme 75).239
Scheme 75. Stereoselective Azidaton of Oridonin and Subsequent CuAAC Reaction of Azides
In the report by Lee and co-workers, salvinorin A 457, potent and selective k-opioid receptor agonist, served as a scaffold for the construction of a few analogues 458 with 1,2,3-triazole and oxadiazole in the place of the furane ring in 457. Unfortunatelly, 5735
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4. CONCLUSION One of the most fascinating challenges in the contemporary organic synthesis and development is the design of efficient synthetic tools which facilitate the access to the molecular diversity and function. One such, perhaps the most successful example of the past decade, is the click chemistry concept. Its pratical emanation is, in particular, the reliable copper(I)catalyzed Huisgen 1,3-dipolar cycloaddition (CuAAC) which generated an enormous output in medicinal, life, and material science. The alkaloids and isoprenoids on the other hand, with their broad biological activities, structural complexity, and high abundance in nature are excellent subjects for click chemistry. In this field, the CuAAC reaction proved to be a convenient and practical tool for modification, assembling, conjugation, or immobilization of these complex natural products. The introduction of the proper 1,2,3-triazole moiety to alkaloid or isoprenoid resulted often in an expected modulation of the existing activity or in an improvement of kinetics, drug release, or cellular uptake. More important, however, is the discovery of many of novel highly active leads based on alkaloids or isoprenoids 1,2,3-triazole. We expect further successful creation of new functions by combining the privileged alkaloid or isoprenoid diversity with the robustness of the CuAAC click chemistry.
these products showed no opioid receptors affinity (Figure 23).240
Figure 23. 1,2,3-Triazole analogues of salvinorin A.
3.4.4. Polyprenoids. Solanesol 459, which is a common polyprenol isolated for example from tobacco leaves, was used by Mash and co-workers for construction of a flexible molecular scaffold decorated by a varying numbers of the terminal alkyne groups for the attachment of a bioactive molecule by the aid of the CuAAC reaction. The desired solanesol-derived alkyne 460 was synthesized in five steps from solanesol, and its application in a covalent multiple and controllable immobilization of peptide melanotropin-derived azide was presented. The resulting multivalent construct 461 showed a similar level of the binding affinity as compared to the corresponding parental ligand with the amino group (CH3(CO)-MSH(4)-NH2)(Scheme 76).241
AUTHOR INFORMATION Corresponding Author
*E-mail:
[email protected]. Tel: +48 61 8291367. Fax: +48 61 829 1505. Notes
The authors declare no competing financial interest.
Scheme 76. Solanesol Scaffold Decorated by Terminal Alkyne Groups for an Attachment of Molecules by the Aid of the CuAAC Reaction
Biographies Karol Kacprzak was born in Toruń, Poland, in 1973. He studied chemistry and molecular biology at the Adam Mickiewicz University in Poznań, Poland. In 2002, he received his Ph.D. from the same institution under the supervision of Prof. Jacek Gawroński, for the work on dyads and triads of Cinchona alkaloids. He then spent two years (2005−2007) as a Marie Curie postdoctoral fellow in Prof. Wolfgang Lindner’s group at Vienna University working on the click-immobilization and synthesis of chiral stationary phases. He is currently assistant professor and head of the Bioorganic Chemistry Department at Adam Mickiewicz University in Poznań. His scientific interests include modern organic, asymmetric, and green synthesis, chiral recognition and enantiomer separation and last but not least natural products and medicinal chemistry. Dr. Iwona Skiera was born in Poznań, Poland. After, she completed her M.Sc. at the Department of Chemistry of Adam Mickiewicz University Poznań, Poland. She received her Ph.D. in Organic Chemistry in 2002 at the University of Poznań. Her research focuses on the synthesis and applications of steroids and alkaloid-derived hybrids and conjugates as well as various aspects of steroids chemistry. Monika Piasecka was born in 1977 in Konin, Poland. She received her M.Sc. degree in organic chemistry in 2001 and her Ph.D. degree in organic chemistry in 2006 from the University of Adam Mickiewicz in Poznań. In the same year, she joined the group of Prof. Zdzisław Paryzek. Her research interests are focused on the synthesis, structure, and recognition properties of bile acids and application of metathesis and click chemistry reactions in steroids chemistry. Prof. Zdzisław Paryzek graduated and received his Ph.D. degree at the Adam Mickiewicz University in Poznań. After two years (1971−1973) as a Postdoctoral Research Fellow with Dr. O. E. (Ted) Edwards at the 5736
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(18) Boren, B. C.; Narayan, S.; Rasmussen, L. K.; Zhang, L.; Zhao, H.; Lin, Z.; Jia, G.; Fokin, V. V. Ruthenium-catalyzed Azide-alkyne Cycloaddition: Scope and Mechanism. J. Am. Chem. Soc. 2008, 130, 8923−8930. (19) Agalave, S. G.; Maujan, S. R.; Pore, V. S. Click Chemistry: 1,2,3Triazoles as Pharmacophores. Chem. - Asian J. 2011, 6, 2696−2718. (20) Moses, J. E.; Moorhouse, A. D. The Growing Applications of Click Chemistry. Chem. Soc. Rev. 2007, 36, 1249−1262. (21) Meldal, M.; Tornøe, C. W. Cu-catalyzed Azide-alkyne Cycloaddition. Chem. Rev. 2008, 108, 2952−3015. (22) Click Triazoles in Topics in Heterocyclic Chemistry; Košmrlj, J., Ed.; Springer, 2012. (23) Schoffelen, S.; Meldal, M. Alkyne-Azide Reactions, in Modern Alkyne Chemistry; Trost, B. M., Li, C.-J., Eds.; Wiley-VCH: Weinheim, 2014. (24) Hou, J.; Liu, X.; Shen, J.; Zhao, G.; Wang, P. G. The Impact of Click Chemistry in Medicinal Chemistry. Expert Opin. Drug Discovery 2012, 7, 489−501. (25) Bock, V. D.; Hiemstra, H.; Van Maarseveen, J. H. CuI-Catalyzed Alkyne−Azide “Click” Cycloadditions from a Mechanistic and Synthetic Perspective. Eur. J. Org. Chem. 2006, 2006, 51−68. (26) Worrell, B. T.; Malik, J. A.; Fokin, V. V. Direct Evidence of a Dinuclear Copper Intermediate in Cu(I)-catalyzed Azide-alkyne Cycloadditions. Science 2013, 340, 457−460. (27) Tron, G. C.; Pirali, T.; Billington, R. A.; Canonico, P. L.; Sorba, G.; Genazzani, A. A. Click Chemistry Reactions in Medicinal Chemistry: Applications of the 1,3-Dipolar Cycloaddition Between Azides and Alkynes. Med. Res. Rev. 2008, 28, 278−308. (28) Thirumurugan, P.; Matosiuk, D.; Jozwiak, K. Click Chemistry for Drug Development and Diverse Chemical-biology Applications. Chem. Rev. 2013, 113, 4905−4979. (29) Lutz, J. F.; Zarafshani, Z. Efficient Construction of Therapeutics, Bioconjugates, Biomaterials and Bioactive Surfaces Using Azide-alkyne ″Click″ Chemistry. Adv. Drug Delivery Rev. 2008, 60, 958−970. (30) Moorhouse, A. D.; Moses, J. E. Click Chemistry and Medicinal Chemistry: a Case of ″Cyclo-addiction″. ChemMedChem 2008, 3, 715− 723. (31) Kolb, H. C.; Sharpless, K. B. The Growing Impact of Click Chemistry on Drug Discovery. Drug Discovery Today 2003, 8, 1128− 1137. (32) Kushwaha, D.; Dwivedi, P.; Kuanar, S. K.; Tiwari, V. K. Click Reaction in Carbohydrate Chemistry: Recent Developments and Future Perspective. Curr. Org. Synth. 2013, 10, 90−135. (33) Witczak, Z. J.; Bielski, R. Click Chemistry in Glycoscience: New Developments and Strategies; Wiley: Hoboken, NJ, 2013. (34) Lallana, E.; Fernandez-Trillo, F.; Sousa-Herves, A.; Riguera, R.; Fernandez-Megia, E. Click Chemistry with Polymers, Dendrimers, and Hydrogels for Drug Delivery. Pharm. Res. 2012, 29, 902−921. (35) Kempe, K.; Krieg, A.; Becer, C. R.; Schubert, U. S. ″Clicking″ on/ with Polymers: a Rapidly Expanding Field for the Straightforward Preparation of Novel Macromolecular Architectures. Chem. Soc. Rev. 2012, 41, 176−191. (36) Yigit, S.; Sanyal, R.; Sanyal, A. Fabrication and Functionalization of Hydrogels through ″Click″ Chemistry. Chem. - Asian J. 2011, 6, 2648−2659. (37) Golas, P. L.; Matyjaszewski, K. Marrying Click Chemistry with Polymerization: Expanding the Scope of Polymeric Materials. Chem. Soc. Rev. 2010, 39, 1338−1354. (38) Binder, W. H.; Sachsenhofer, R. ‘Click’ Chemistry in Polymer and Materials Science. Macromol. Rapid Commun. 2007, 28, 15−54. (39) Nandivada, H.; Jiang, X.; Lahann, J. Click Chemistry: Versatility and Control in the Hands of Materials Scientists. Adv. Mater. 2007, 19, 2197−2208. (40) Lahann, J. Click Chemistry for Biotechnology and Materials Science; Wiley: Chichester, 2009. (41) Fournier, D.; Hoogenboom, R.; Schubert, U. S. Clicking Polymers: a Straightforward Approach to Novel Macromolecular Architectures. Chem. Soc. Rev. 2007, 36, 1369−1380.
Division of Biological Sciences, National Research Council of Canada, Ottawa, he came back to his Alma Mater Posnaniensis and became Associate Professor in 1979. Since 1991, he has been full Professor of chemistry. He has held the position of visiting professor at the University of Florida, Gainesville, Florida, visiting scientist at Division of Chemistry, NRC Canada, Ottawa, and University of Western Ontario, Ontario, Canada. His research interests include organic synthesis, steroid and triterpenoid chemistry, cycloaddition reactions, ozonolysis with nucleophilic participation, cyclobutanone chemistry, and bile acids as supramolecular scaffolds.
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