Technical Advances in Medicinal Chemistry - ACS Combinatorial

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Editorial pubs.acs.org/acscombsci

Technical Advances in Medicinal Chemistry

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ombinatorial synthetic chemistry started as a way to increase the pace of discovery of biologically active molecules, with the expectation that a bigger pipeline would give rise to more and better medicines. While the accuracy of this prediction may be debated, combinatorial synthesis has become a widely used tool in academic and industrial laboratories alike. And as with many bold initiatives, the grand scope of the enterprise gave rise to unanticipated advances in related fields, many of them in the testing and analysis of molecular function. We focus in this virtual issue on new and developing tools that are changing the way medicinal chemistry is practiced. Three of the journals contributing to this issue, the Journal of Medicinal Chemistry, ACS Medicinal Chemistry Letters, and Chemical Reviews, usually focus on the “what” and the “why” new information, insights, and molecules of relevance to the field. ACS Combinatorial Science, in contrast, focuses to a great extent on the “how.” Of course, each subject contains important contributions from the others, and indeed, most of the twenty-six papers collected here could have appeared, with only modest changes, in at least two of the four journals. Such is the interdisciplinary nature of modern drug discovery. The emphasis here is on ways in which technology continues to enable the rapid acquisition of important information on relevance to medicinal chemistry. With apologies for some necessary oversimplification, they can be grouped in the themes of generating interesting matter, and figuring out what it does. Often, speed and success are enhanced by doing both at the same time or in parallel. Thus, work continues to be done worldwide on the rapid generation of candidate molecules, by new techniques of chemical synthesis on the bench and by modules taken from biological systems. Here, the reader will find examples of new or optimized synthetic methods,1,2 purification techniques,3,4 the use of privileged molecular fragments,5 including their evaluation by computational methods,6 and advanced ways to correlate preparation with preliminary screening in efficient fashion.7−9 An excellent example of the merging of previously disparate fields enabling both synthesis and screening is the rise of DNA-encoded synthesis, represented by four recent contributions.10−13 Peptides continue to be popular as an informationrich motif amenable to facile synthesis and modification.14,15 Analytical methods are also critically important. In this collection, they are represented by physical methods that can correlate to biological properties,16−22 and by methods that test function in biological environments.23−25 In the dawning age of personalized medicine and the accelerating one of microbial adaptation, medicinal chemistry remains of paramount importance. We hope that readers will find this collection illuminating, as an example of the reinforcing roles that chemists of many subspecialties can play.

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REFERENCES

(1) Tucker, J. W.; Chenard, L.; Young, J. M. Selective Access to Heterocyclic Sulfonamides and Sulfonyl Fluorides via a Parallel Medicinal Chemistry Enabled Method. ACS Comb. Sci. 2015, 17 (11), 653−657. (2) Xia, L.; Idhayadhulla, A.; Lee, Y. R.; Kim, S. H.; Wee, Y.-J. Microwave-Assisted Synthesis of Diverse Pyrrolo[3,4-c]quinoline-1,3diones and Their Antibacterial Activities. ACS Comb. Sci. 2014, 16 (7), 333−341. (3) Goetz, G. H.; Philippe, L.; Shapiro, M. J. EPSA: A Novel Supercritical Fluid Chromatography Technique Enabling the Design of Permeable Cyclic Peptides. ACS Med. Chem. Lett. 2014, 5 (10), 1167−1172. (4) Stalder, R.; Roth, G. P. Preparative Microfluidic Electrosynthesis of Drug Metabolites. ACS Med. Chem. Lett. 2013, 4 (11), 1119−1123. (5) Joshi, P.; Chia, S.; Habchi, J.; Knowles, T. P. J.; Dobson, C. M.; Vendruscolo, M. A Fragment-Based Method of Creating SmallMolecule Libraries to Target the Aggregation of Intrinsically Disordered Proteins. ACS Comb. Sci. 2016, 18 (3), 144−153. (6) Mehra, R.; Rani, C.; Mahajan, P.; Vishwakarma, R. A.; Khan, I. A.; Nargotra, A. Computationally Guided Identification of Novel Mycobacterium tuberculosis GImU Inhibitory Leads, Their Optimization, and in Vitro Validation. ACS Comb. Sci. 2016, 18 (2), 100− 116. (7) Tréguier, B.; Lawson, M.; Bernadat, G.; Bignon, J.; Dubois, J.; Brion, J.-D.; Alami, M.; Hamze, A. Synthesis of a 3-(alphaStyryl)benzo[b]-thiophene Library via Bromocyclization of Alkynes and Palladium-Catalyzed Tosylhydrazones Cross-Couplings: Evaluation as Antitubulin Agents. ACS Comb. Sci. 2014, 16 (12), 702−710. (8) Yu, G.; Kuo, D.; Shoham, M.; Viswanathan, R. Combinatorial Synthesis and in Vitro Evaluation of a Biaryl Hydroxyketone Library as Antivirulence Agents against MRSA. ACS Comb. Sci. 2014, 16 (2), 85− 91. (9) Xiang, J.; Zhang, Z.; Mu, Y.; Xu, X.; Guo, S.; Liu, Y.; Russo, D. P.; Zhu, H.; Yan, B.; Bai, Xu Discovery of Novel Tricyclic Thiazepine Derivatives as Anti-Drug-Resistant Cancer Agents by Combining Diversity-Oriented Synthesis and Converging Screening Approach. ACS Comb. Sci. 2016, 18 (5), 230−235. (10) Malone, M. L.; Paegel, B. M. What is a “DNA-Compatible” Reaction? ACS Comb. Sci. 2016, 18 (4), 182−187. (11) MacConnell, A. B.; McEnaney, P. J.; Cavett, V. J.; Paegel, B. M. DNA-Encoded Solid-Phase Synthesis: Encoding Language Design and Complex Oligomer Library Synthesis. ACS Comb. Sci. 2015, 17 (9), 518−534. (12) Harris, P. A.; King, B. W.; Bandyopadhyay, D.; Berger, S.; Campobasso, N.; Capriotti, C. A.; Cox, J. A.; Dare, L.; Dong, X.; Finger, J. N.; Grady, L. C.; Hoffman, S. J.; Jeong, J. U.; Kang, J.; Kasparcova, V.; Lakdawala, A. S.; Lehr, R.; McNulty, D. E.; Nagilla, R.; Ouellette, M. T.; Pao, C. S.; Rendina, A. R.; Schaeffer, M. C.; Summerfield, J. D.; Swift, B. A.; Totoritis, R. D.; Ward, P.; Zhang, A.; Zhang, D.; Marquis, R.W.; Bertin, J.; Gough, P. J. DNA-Encoded Library Screening Identifies Benzo[b][1,4]oxazepin-4-ones as Highly Potent and Monoselective Receptor Interacting Protein 1 Kinase Inhibitors. J. Med. Chem. 2016, 59, 2163−217. (13) Wu, Z.; Graybill, T. L.; Zeng, X.; Platchek, M.; Zhang, J.; Bodmer, V. Q.; Wisnoski, D. D.; Deng, J.; Coppo, F. T.; Yao, G.; Tamburino, A.; Scavello, G.; Franklin, G. J.; Mataruse, S.; Bedard, K. L.; Ding, Y.; Chai, J.; Summerfield, J.; Centrella, P. A.; Messer, J. A.;

AUTHOR INFORMATION

Notes

Views expressed in this editorial are those of the author and not necessarily the views of the ACS. © XXXX American Chemical Society

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DOI: 10.1021/acscombsci.7b00053 ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science

Editorial

Pope, A. J.; Israel, D. I. Cell-Based Selection Expands the Utility of DNA-Encoded Small-Molecule Library Technology to Cell Surface Drug Targets: Identification of Novel Antagonists of the NK3 Tachykinin Receptor. ACS Comb. Sci. 2015, 17 (12), 722−731. (14) Azmi, S.; Jiang, K.; Stiles, M.; Thundat, T.; Kaur, K. Detection of Listeria monocytogenes with Short Peptide Fragments from Class Ha Bacteriocins as Recognition Elements. ACS Comb. Sci. 2015, 17 (3), 156−163. (15) Trinh, T. B.; Upadhyaya, P.; Qian, Z.; Pei, D. Discovery of a Direct Ras Inhibitor by Screening a Combinatorial Library of CellPermeable Bicyclic Peptides. ACS Comb. Sci. 2016, 18 (1), 75−85. (16) Marholz, L. J.; Wang, W.; Zheng, Yu; Wang, X. A Fluorescence Polarization Biophysical Assay for the Naegleria DNA Hydroxylase Tet1. ACS Med. Chem. Lett. 2016, 7 (2), 167−171. (17) Tipping, W. J.; Tshuma, N.; Adams, J.; Haywood, H. T.; Rowedder, J. E.; Fray, M. J.; McInally, T.; Macdonald, S. J. F.; Oldham, N. J. Relative Binding Affinities of Integrin Antagonists by Equilibrium Dialysis and Liquid Chromatography−Mass Spectrometry. ACS Med. Chem. Lett. 2015, 6 (2), 221−224. (18) Woods, L. A.; Dolezal, O.; Ren, B.; Ryan, J. H.; Peat, T. S.; Poulsen, S.-A. Native State Mass Spectrometry, Surface Plasmon Resonance, and X-ray Crystallography Correlate Strongly as a Fragment Screening Combination. J. Med. Chem. 2016, 59, 2192− 2204. (19) Espada, A.; Broughton, H.; Jones, S.; Chalmers, M. J.; Dodge, J. A. A Binding Site on IL-17A for Inhibitory Macrocycles Revealed by Hydrogen/Deuterium Exchange Mass Spectrometry. J. Med. Chem. 2016, 59, 2255−2260. (20) Zhang, T.; Liu, Y.; Yang, X.; Martin, G. E.; Yao, H.; Shang, J.; Bugianesi, R. M.; Ellsworth, K. P.; Sonatore, L. M.; Nizner, P.; Sherer, E. C.; Hill, S. E.; Knemeyer, I. W.; Geissler, W. M.; Dandliker, P. J.; Helmy, R.; Wood, H. B. Definitive Metabolite Identification Coupled with Automated Ligand Identification System (ALIS) Technology: A Novel Approach to Uncover Structure-Activity Relationships and Guide Drug Design in a Factor IXa Inhibitor Program. J. Med. Chem. 2016, 59, 1818−1829. (21) von Kleist, L.; Michaelis, S.; Bartho, K.; Graebner, O.; Schlief, M.; Dreger, M.; Schrey, A. K.; Sefkow, M.; Kroll, F.; Koester, H.; Luo, Y. Identification of Potential Off-target Toxicity Liabilities of CatecholO-methyltransferase Inhibitors by Differential Competition Capture Compound Mass Spectrometry. J. Med. Chem. 2016, 59, 4664−4675. (22) Yao, J.; Yang, M.; Duan, Y. Chemistry, Biology, and Medicine of Fluorescent Nanomaterials and Related Systems: New Insights into Biosensing, Bioimaging, Genomics, Diagnostics, and Therapy. Chem. Rev. 2014, 114, 6130. (23) (a) Bertrand, S. M.; Ancellin, N.; Beaufils, B.; Bingham, R. P.; Borthwick, J. A.; Boullay, A.-B.; Boursier, E.; Carter, P. S.; Chung, C.w.; Churcher, I.; Dodic, N.; Fouchet, M.-H.; Fournier, C.; Francis, P. L.; Gummer, L. A.; Herry, K.; Hobbs, A.; Hobbs, C. I.; Homes, P.; Jamieson, C.; Nicodeme, E.; Pickett, S. D.; Reid, I. H.; Simpson, G. L.; Sloan, L. A.; Smith, S. E.; Somers, D. O'N.; Spitzfaden, C.; Suckling, C. J.; Valko, K.; Washio, Y.; Young, R. J. The Discovery of in Vivo Active Mitochondrial Branched-Chain Aminotransferase (BCATm) Inhibitors by Hybridizing Fragment and HTS Hits. J. Med. Chem. 2015, 58, 7140−7163. (b) Scanlon, M. Inhibitors of BCATm: A Tough Nut To Crack. J. Med. Chem. 2015, 58, 7138−7139. (24) Uddin, Md. J.; Crews, B. C.; Huda, I.; Ghebreselasie, K.; Daniel, C. K.; Marnett, L. J. Trifluoromethyl Fluorocoxib A Detects Cyclooxygenase-2 Expression in Inflammatory Tissues and Human Tumor Xenografts. ACS Med. Chem. Lett. 2014, 5 (4), 446−450. (25) Quartararo, C. E.; Reznik, E.; de Carvalho, A. C.; Mikkelsen, T.; Stockwell, B. R. High-Throughput Screening of Patient-Derived Cultures Reveals Potential for Precision Medicine in Glioblastoma. ACS Med. Chem. Lett. 2015, 6 (8), 948−952.

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DOI: 10.1021/acscombsci.7b00053 ACS Comb. Sci. XXXX, XXX, XXX−XXX