Medicinal Inorganic Chemistry - American Chemical Society

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Chapter 16

Heme as Trigger and Target of the Antimalarial Peroxide Artemisinin 1

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Anne Robert , Françoise Benoit-Vical , and Bernard Meunier 1

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Laboratóire de Chimie de Coordination du CNRS, 205 route de Narbonne, 31077 Toulouse Cedex 4, France C H U Rangueil-Parasitologie, 1 Avenue Jean Poulhès, TSA 50032, 31059 Toulouse Cedex 9, France 2

The present review is focused on the mechanism of action of artemisinin, a peroxide-containing antimalarial drug. Upon reductive activation by iron(II)-heme, artemisinin is transformed to a reactive C4-centered radical species able to efficiently alkylate the heme-macrocycle itself. On the basis of this reactivity, which is probably pharmacologically relevant, a family of new antimalarial drugs named Trioxaquines have been synthesized. Trioxaquines combine, within a single molecule, two pharmacologically active moieties acting on the same target, heme, by two different mechanisms: a 4aminoquinoline, present in the conventional antimalarial chloroquine, and an endoperoxide responsible for the activity of artemisinin. Several trioxaquines are active in vitro on chloroquine-resistant malaria parasite at nanomolar concentration, and are efficient to cure by oral administration malaria-infected mice at 20-50 mg/kg. ®

© 2005 American Chemical Society

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Metals in medicine: role of metal ions in drug-design At the interface of inorganic chemistry and biology, the discovery and the rational design of metal-based drugs is a growing field among academic researchers with some spectacular large-scale medical applications (cw-platinum and contrast agents for magnetic resonance imaging). For these complexes which are currently used in medical applications, the metal center plays a key role and is responsible for the observed pharmacological and biological effects (i, 2). Besides this main category, some organic drugs should be activated in vivo by a metal center in order to generate the pharmacological reactive entities. This is true for organic drugs that have to be activated by cytochrome P450 enzymes, but also for few drugs that interact with a metal complex acting as trigger and target. This latter category of drugs is clearly exemplified by artemisinin and its mechanism of action related to the hemoglobin digestion in red blood cells infected by Plasmodium, the parasite responsible for malaria.

Heme in Malaria Infected Red Blood Cells After a mosquito bite, the malaria parasites first invade the liver and replicate within red blood cells. Many antimalarial drugs are specifically active against the blood stage of the parasite life within humans (3).

Digestion of Hemoglobin Within infected erythrocytes, Plasmodium falciparum (strain responsible for most fatal cases) digest the host hemoglobin with the aid of several specific parasite proteases (¥, J). Hemoglobin comprises 95% of the cytosolic protein of red blood cells and up to 80% of the 5 m M hemoglobin is degraded by the parasite (6). This intensive proteolysis releases free heme and amino-acids. These amino-acids are incorporated into parasitic proteins and this supply is essential for the survival of Plasmodium, a "true parasite", which has a limited capacity for the de novo amino-acid synthesis. Only a very limited amount of the free heme is metabolized by the parasite as iron source.

Heme Aggregation In hemoglobin, iron is essentially in die ferrous state. Upon degradation of the globin and the release of heme, this iron(II)-protoporphyrin(IX) is able to transfer one electron to molecular oxygen to produce superoxide radicals, hydrogen peroxide and, finally, hydroxyl radicals, generating a lethal oxidative

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stress for the parasite which lacks heme oxygenase that vertebrates use for heme catabolism. As a detoxification process, heme is oxidized and aggregated into a redox inactive iron(III) crystalline material called hemozoin (7). Hemozoin is primarily formed by dimerization of heme, a carboxylate function of a heme molecule A being axial ligand of iron(III) of a second heme molecule B, and a carboxylate of Β being axial ligand of the iron(III) of A. These dimers aggregate through hydrogen bonds of the remaining free carboxylates, leading to heme aggregation as a crystalline, insoluble material. Hemozoin is not a "covalent polymer", but an aggregate of dimers, and the parasitic proteins involved in its formation are not polymerases. Any perturbation of this heme-detoxification process that is unique to Plasmodium is expected to have drastic consequences for the parasite survival. The inhibition of heme aggregation is the targeted action of conventional quinoline based antimalarial drugs such as quinine, chloroquine and mefloquine.

Reactivity of artemisinin in the presence of heme Artemisinin, a sequiterpene with a trioxane entity (see Figure 1 for structure), exhibits a chemical structure very different compared to that of the other known antimalarial drugs and is thus likely to have a different mechanism of action. Among antimalarial drugs, artemisinin (8) (and its hemisynthetic derivatives artemether, arteether, and artesunate, obtained by reduction of the lactone to the lactol, dihydroartemisinin, followed by functionalization) retains efficacy against multidrug resistant parasite strains, and no clinically relevant drug-resistance has yet been reported, despite an increased use over the past two decades (9). Artemisinin derivatives have been proven to be safe, even for young children and pregnant women. However, when used as monotherapy, they are associated with a high recrudescence rate (that should not be mistaken for inherent parasite resistance) due to their short half-lives (10). Artemisinin derivatives are therefore being used in combination with longer half-life drugs to increase the efficacy of the treatment (77, 12). The pharmacological activity of artemisinin derivatives lies in their peroxide function, the deoxyartemisinin being completely devoid of biological activity (73). When malaria parasites are incubated in the presence of [ C]artemisinin, the radioactivity is associated with covalent drug adducts with hemozoin (14) and with a few number of specific parasite proteins (75, 16). One of these alkylated proteins is a malarial translationally controlled tumor protein (TCTP) homolog of yet unknown function (77). The selective inhibition PCATP6, a sarco/endoplasmic reticulum Ca -ATPase, by artemisinin has been recently reported (18). Interestingly, the reaction of these proteins with artemisinin depends on the presence of iron(II)-heme in the case of TCTP, or on an unidentified iron(II) species in the case of PfATP6. 14

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Heme-artemisinin covalent adducts The importance of alkylating species generated by iron-mediated homolytic cleavage of the endoperoxide function of artemisinin, in particular the alkyl radical centered at position C4 of artemisinin or related trioxanes, was early proposed (19). After preliminary experiments with synthetic metalloporphyrins (20), we have reported that, when iron(III)-protoporphyrin(IX) was incubated with artemisinin in the presence of glutathione, heme was readily converted in high yield to heme-artemisinin covalent adducts, resulting from alkylation of the four meso positions of the heme ligand by the C4 alkyl radical derived from artemisinin (Figure 1) (21-23). After demetallation of the heme moiety, complete NMR characterization of these heme-artemisinin covalent adducts was obtained (24).

Figure 1: Alkylation of heme by artemisinin. Similar alkylation of the heme moiety has been observed in the presence of artemether (21). In addition, by studying the reactivity of a large series of trioxanes (20, 25, 26), it has been possible to correlate their alkylating ability

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toward a heme model, manganese(II) tetraphenylporphyrin, and their pharmacological activity: Efficient antimalarial drugs behave as good alkylating agents and most of the inactive drugs were unable to alkylate the porphyrin ring. Furthermore, it appeared that trioxanes bearing a bulky methyl substituent at C4 on the α face of the endoperoxide (i.e. on the same side than the peroxide with respect to the mean drug plane), were at the same time inactive on infected red blood cells and unable to alkylate the porphyrin cycle (Figure 2) (25). (a) Case of active trioxanes: in the case of artemisinin, the R substituent between C12 and C8a stands for the lactone ring

H C 3

1. Inner-sphere electron transfer

2. Homolytic O-O bond cleavage

(a) Case of inactive trioxanes: the close interaction between Mn and 01 is prevented by a ct-substituent at C4 n

H C 3

3. C - C bond p-scission No activation of the peroxide

Heme alkylation

Figure 2: Activation of trioxanes via an inner-sphere electron tranfer. Possible correlation between pharmacological activity and alkylating ability. Reprinted with permissionfromreference 23. Copyright (2002) American Chemical Society. An analog trioxane with a methyl-C4 on the ß-face, was active on malaria parasites and, at the same time, able to alkylate Mn TPP. Trioxanes without substituent at C4, whatever the substituents on other positions (for example methoxy at C12) were α or β, were pharmacologically active and able to alkylate Mn TPP. This indicates that the difference of reactivity of epimers at n

n

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C4 is probably due to the difference of interaction with the metal center, more than to other possible factors, say transport, competitive detoxification... This data confirmed that (i) a close interaction between the reducing metal center and the peroxide is required, suggesting that this activation occurred through an inner-sphere electron transfer, (ii) only active endoperoxides alkylate heme or metalloporphyrin while inactive ones do not, suggesting that this alkylation reaction is probably important in parasite killing. In addition, these artemisinin-heme adducts appear to be generated in artemisinin-treated parasites (14).

Possible pharmacological role of the heme-artemisinin adducts How can the alkylation of heme by artemisinin kill the parasite? Plasmodium falciparum's histidine-rich protein (PfHRP-II) promotes the formation of hemozoin. This protein contains repeats of the sequence His-HisAla, together histidine and alanine making up 76% of the mature protein (27). HRP is able to bind approximately 50 molecules of heme at pH 7 (28% and 17 at pH 4.8, thus acting as a scaffold for heme, important in the initiation of hemozoin chains (29). Recent studies suggest that the heme-artemisinin adducts (Figure 1) are able to bind to PfHRP-II with a higher affinity than heme itself, displace heme from PfHRP-II, and that either low pH or chloroquine dissociates heme but not heme-artemisinin adductsfromPfHRP-II (30). The binding of heme-artemisinin adducts to HRP-II with high affinity constants may result in the inhibition of hemozoin formation leading to the building-up of the concentration offreeheme within the parasite. At micromolar concentrations, artemisinin inhibits hemozoin formation (30, 31), but this has only been demonstrated in cell-free conditions, and remains controversial: artemisinin treatment of living parasites caused no measurable change in hemozoin content (32). However, the concentration of the heme pool (hemoglobin + free heme) that can be accumulated within the digestive vacuole during hemoglobin degradation can be as high as 400 mi7/imolar (33). One has to keep in mind thatfreeheme at micromohx concentration can damage cellular metabolism (6). Consequently, a very small portion of heme that escapes to the aggregation process (for example, 1 heme molecule over 10 or 10 ) should be sufficient to kill the parasite without having detectable effect on the hemozoin accumulation. 4

s

Heme-quinoline interactions It has been underlined that the antimalarial activity of quinoline-based drugs (quinine, chloroquine, mefloquine) also depend on their interactions with heme, thus preventing aggregation of toxic heme released during proteolysis of hemoglobin by the parasite. In vitro, efficient quinolines block the aggregation

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287 of micromolar heme into hemozoin under approximated physiological conditions mediated by crude trophozoite lysates, seed crystals of hemozoin, or Plasmodium falciparum-denved HRPs. However, contrary to the covalent bond between heme and artemisinin, chloroquine and its congeners bind heme non covalently. Chloroquine has a high affinity for ferric heme (Kd = 3.5 nM), and ring-ring π-stacking of the quinoline nucleus with the porphyrin macrocycle has been observed by NMR (34, 35). In vitro, quinolines do not bind directly to the HRPs nor do they interact with isolated hemozoin. These results suggest that quinoline-heme complexes are incorporated into the growing aggregate to terminate the chain extension of hemozoin, blocking further sequestration of toxic heme and poisoning the parasite with its own waste (6, 33). The interaction of chloroquine with iron(III)-heme requires an extensive degradation of the globin or, at least, release of the heme moiety from the protein. On the contrary, artemisinin may be activated by iron(II)-heme whenever one side of the heme nucleus is accessible for endoperoxide approach and activation. We recently found that alkylation of heme occurred in 25% yield by incubation of artemisinin with human ferrous hemoglobin A in the absence of protease activity, under non denaturing conditions, or even when artemisinin was incubated with hemolyzed human blood (36).This is consistent with the antimalarial activity of artemisinin on early intra-erythrocytic stages of the parasite, whereas quinoline inhibition is specific for parasite stages that are actively degrading hemoglobin. 0

Other targets, other trigger(s) for artemisinin ? In pioneer work, Meshnick and collaborators reported that, when Plasmodium falciparum-infected red blood cells was incubated with radiolabeled artemisinin derivatives, dihydroartemisinin, or arteether, drug derived radioactivity was found to be concentrated in the isolated parasites. In spite the difficulties to prepare protein-free hemozoin, radioactivity was associated, on one side, with heme and, on the other side, with specific parasitic membrane proteins, probably via alkylation. The reaction appears to be specific, since the alkylated proteins are not the most abundant in isolated parasites. It is likely that it is pharmacologically relevant, since all the active peroxides alkylate the same proteins and none of them were alkylated by the biologically inactive deoxyarteether (15). At this stage, the identities or fimctions of the alkylated proteins was unknown. One of the most heavily labeled proteins was later isolated from parasite grown in the presence of [ H]dihydroartemisinin (300 mM) and identified as a 25-kDa translationally controlled tumor protein (TCTP) homolog, that is able to bind heme with modest affinity (17). In vitro, the reaction of dihydroartemisinin with recombinant TCTP is clearly dependent on the presence of heme; the single cysteine of the protein also appears to be necessary for the reaction, probably serving as a source of electrons for the heme-mediated activation of die drug. 3

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Although it is difficult to understand how alkylation of TCTP could kill the parasite because little is known about the physiological roles of this protein, the fact that this reaction occurs both in vitro and in vivo suggests that it is biologically relevant. It was also reported that a high concentration of artemisinin (200 μΜ) inhibits the cysteine protease activity of vacuolar extracts of Plasmodium, involved in digestion of hemoglobin, but does not interfere with the activity of aspartic proteases that are responsible for the initial cleavage of the globin chain into large peptidefragments(51). Recently, Ca -dependent ATPase activity of PfATP6, the only SERCAtype Ca -ATPase of Plasmodium, was shown to be abolished by active artemisinin derivatives, but not by deoxyartemisinin, quinine or chloroquine. On the contrary, artemisinin has no influence on the activity of a mammalian SERCA Ca -ATPase, and several Plasmodium proteins including a nonSERCA-type ATPase and a glucose transporter (18). PfATP6 was expressed in Xenopus laevis oocytes, a heme free medium. However, the iron chelator desferrioxamine significantly abrogated the inhibition of PfATP6 by artemisinin, suggesting that an unidentified iron species was this time responsible for the activation of artemisinin, leading to drug-derived radical species. In all the reports on the interaction of artemisinin with biomolecules, there is strong evidence that drug-derived alkylating species are involved. There is both biological and chemical evidence for the role of heme in reductive activation of artemisinin, and the characterization of heme-artemisinin adducts shows that heme can be both the trigger and the target of artemisinin. But there is also evidence that heme is not the single target nor, maybe, the single trigger of antimalarial endoperoxides: other biological reducing iron species may play a similar role, leading to the alkylation of the protein(s) where they are located.

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Other antimalarial drugs with the same mechanism ? Synthetic trioxanes, simplified analogs of artemisinin, supposed to act in the same way, have also been developed (37). Future studies will provide information on the pharmacokinetics parameters of these artemisinin mimicks and tell us if these molecules have longer half-life times in plasma. Recently, chloroquine has been successfully modified with a ferrocenyl entity incorporated within the side chain of the drug. This drug named ferroquine is active against chloroquine-resistant strains of the malaria parasite (38). This molecule is an example of the development of bioorganometallic chemistry in the design of drugs.

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New molecules for an old target: Trioxaquines The combination of artemisinin derivatives with a second drug having a different mode of action is increasingly seen as the best way to prevent the emergence and spread of drug resistance, and to interrupt the transmission of P. falciparum (11, 39). Keeping in mind that chloroquine and artemisinin both interact with heme, but by two different mechanisms, we prepared new chimeric molecules, named trioxaquines®, by covalent attachment of a trioxane moiety to a 4-aminoquinoline (Figure 3) (40). Trioxaquines combine, within a single molecule, a aminoquinoline, known to easily accumulate within infected erythrocytes, and a peroxide acting as a potential alkylating species after reductive activation.

Figure 3. Trioxaquines are dual antimalarial molecules. In order to get easily accessible molecules, a convergent synthesis based on classical reactions was used, starting from cheap materials. The synthesis of a second-generation trioxaquine (DU1301) is depicted in Figure 4.

c/s-trioxane

Figure 4. Convergent synthesis of Trioxaquine DU1301. In trioxaquine DU1301, the amine and the peroxide substituents can be trans or eis with respect to the cyclohexane ring. The reductive amination reaction therefore provided two diastereomeric racemates trans-D\]\30l and ds-DU1301 (50/50) (Figure 5). For structure elucidation and biological evaluation, the two diastereomers of

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D U 1301 have been separated and their structures determined by X-ray diffraction. The structure of trans-DO\30l is depicted in Figure 6 (41). Many modulations of the trioxaquine structure are possible (quinoline, diene, linker), and a number of them have been made, leading to a large family of new antimalarial compounds that are now under biological investigation.

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Trans-DU1301 amine atC17is:

CJS-DU1301 amine atC17is:

peroxide atC3is:

^equatorial ~ ~ equatorial stable conformer

peroxide a t C 3 is:

equatorial /

(A)

(C)

c

8

QuitiNH equal" QuinN! equal

χ axial****** equatorial

fc

axiaUwv> axial not detected

QuinlsiH

axial

Figure 5. The two diastereomeric racemates of DU 1301, the amine and the peroxide function being either axial or equatorial with respect to the cyclohexane ring. Quin-NH refers to the aminoquinoline residue.

Figure 6. X-ray structure of trans-DU1301 (conformer C).

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Antimalarial activity of trioxaquines Trioxaquines have modular structures linking two different moieties. A study of the relation between the structure of the trioxaquines and their antiplasmodial activities in vitro and in vivo was done. All the trioxaquines tested in vitro present interesting antimalarial properties on strains of Plasmodium falciparum chloroquine-sensitive and chloroquine-resistant with IC50 inferior to 100 nM and around 10 nM for the best trioxaquines (41). The trioxaquines DU1302 (citrate salt of the base form DU1301) and DU 1102 (see ref. 40 for the structure of this first-generation trioxaquine) showed the most promising antimalarial activities. Their IC o values ranged from 6 to 17 nM and from 22 to 27 nM respectively, whatever the chloroquine sensitivity of the strains used. These values are very similar to artemisinin activity (IC o on the same strains: 5-8 nM) and largely better than chloroquine (62-174 nM). The trioxaquine DU 1102 is highly active against Cameroonian isolates as well (42). The mean IC o obtained on 32 different P. falciparum isolates is 43 nM (ranging from 11 to 71 nM). There is no significant difference between the mean of DU 1102 for chloroquino-sensitive (48 nM) and chloroquino-resistant (40 nM) isolates. There is no correlation between the response to DU1102 and chloroquine and a low correlation with pyrimethamine, suggesting independent modes of action of the trioxaquine against the parasite. Because trioxaquine DU1302 showed the best antimalarial activity, more chemical and biological investigations have been performed (41). As explained above and in Figure 5 for trioxaquine DU1301, its citrate salt DU1302 exists as two diastereomeric racemates that have been independently tested in vitro on P. falciparum. The iraras-DU1302, the c/s-DU1302, and the 50/50 mixture of both diastereomers exhibit in vitro similar activities with IC50 values being 7-19 nM, 5-11 nM, and 6-17 nM, respectively. In addition, it should be noted that trioxaquines have better activities on highly chloroquine-resistant strains of the parasite. DU1302 has been selected for the evaluation of its antimalarial activity in vivo on mice infected by P. vinckei in a 4-day suppressive test (43). DU1302 presents a potent antimalarial activity with ED o values of 5 mg/kg/d and 18 mg/kg/d, by intraperitoneal and oral administration, respectively. These values are in the range of that reported for artemisinin itself. Moreover, complete cures of parasitemia without recrudescence have been observed at 20 (ip route) and 50 mg/kg/d (oral route) (i.e. no detected parasite after 60 days). An absence of toxicity by oral route of DU1302 during 60 days has been observed both on non-infected mice treated with 100 mg/kg/d for three consecutive days and on infected mice treated with 120 mg/kg/d for four days. Finally, the genotoxicity of DU 1302 has been evaluated. Drugs that damage DNA induce systems of DNA repair such as the SOS-response, and the ability to induce this phenomenon in Escherichia coli has been shown to be correlated to the genotoxicity in human (44). The possible induction of the SOS5

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292 response to DU1302 in Ε coli (using the anti-cancer drug mitomycin C as control) has been studied. Whereas mitomycin C is found genotoxic at 3 μΜ, the trioxaquine DU1302 was unable to induce the SOS-response in E. coli up to 20 μΜ, a concentration 1000 times higher than its antimalarial IC o values, indicating the absence of in vitro genotoxicity for this trioxaquine. Furthermore, DU1302 is a stable compound, either at room temperature in air for more than six months, in an acidic solution for three days, or at 60 °C in air for 24 h. In summary, the high efficacy in vitro and in vivo of DU1302 (in particular on chloroquine-resistant strains), its easy synthesis, its chemical stability, and its absence of toxicity and genotoxicity make this trioxaquine a promising drugcandidate for antimalarial therapy.

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Conclusion This report on the mechanism of action of antimalarial artemisinin derivatives and the design of trioxaquines is an example of the key role of a biological metal complex (heme in the present case) acting both as trigger and target for the drug.

Acknowledgements A l l co-authors of the articles signed by AR, FBV and B M are warmly acknowledged for their key contributions on the mechanism of action of artemisinin derivatives and for the preparation and biological evaluation of trioxaquines. This work has been supported by the CNRS, the Rogion MidiPyrinies and P A L U M E D . This start-up company and SANOFISYNTHELABO are currently working on the development of trioxaquines. The authors are grateful to Jean-Paul Soguela, Jean-Francis Magnaval and Antoine Berry (CHU-Rangueil, Departement of Parasitology) for many discussions on malaria therapy. Heinz Gornitzka (Universite Paul Sabatier - CNRS Toulouse) is gratefully acknowledged for the X-ray determination of several trioxaquine and trioxane derivatives.

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In Medicinal Inorganic Chemistry; Sessler, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005.