Heterocyclization vs Coupling Reactions: A DNA-Encoded Libraries Case

Authors

DOI:

https://doi.org/10.24959/ophcj.23.275133

Keywords:

DNA-encoded libraries technology, orthogonal functional groups, coupling reactions, polyfunctional building blocks, heterocyclizations, chemoinformatics, scaffold diversity

Abstract

Aim. DNA-encoded libraries technologies (DELT) are gradually becoming an important part of standard drug discovery toolbox. DELT is looking to find its place between classic low-molecular-weight drug candidates on the one hand, and high-molecular-weight antibodies and peptides on the other hand. On its natural path to overcoming the “childhood diseases” typical for every novel technology, DELT has reached a point where the chemical diversity of DNA-encoded libraries (DELs) becomes an important factor to look out for. In this paper, we aim to take a closer look at the chemical diversity of DELs in their present state and find the ways to improve it.
Results and discussion. We have identified the DEL-viable building blocks from the Enamine Ltd. stock collection, as well as from Chemspace Ltd. virtual collection, using the SMARTS set, which takes into account all the necessary structural restrictions. Using modern cheminformatics tools, such as Synt-On, we have analyzed the scaffold diversity of both stock and virtual core bi- and tri-functional building blocks (BBs) suitable for DNA-tolerant reactions. The identification of scaffolds from the most recently published on-DNA heterocyclization reactions and analysis of their inclusion into the existing BBs space have shown that novel DNA-tolerant heterocyclizations are extremely useful for expanding chemical diversity in DEL technologies.
Conclusions. The analysis performed allowed us to recognize which functional groups should be prioritized as the most impactful when the new BBs are designed. It is also made clear that the development of new DNA-tolerant reactions, including heterocyclizations, have a significant potential to further expand DEL molecular diversity.

Supporting Agency

  • The authors received no specific funding for this work.

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References

  1. Brenner, S.; Lerner, R. A. Encoded combinatorial chemistry. Proceedings of the National Academy of Sciences 1992, 89 (12), 5381-5383. https://doi.org/10.1073/pnas.89.12.5381.
    |
  2. Goodnow, R. A., Jr.; Dumelin, C. E.; Keefe, A. D. DNA-encoded chemistry: enabling the deeper sampling of chemical space. Nat. Rev. Drug Discov. 2017, 16 (2), 131-147. https://doi.org/10.1038/nrd.2016.213.
    |
  3. Satz, A. L.; Brunschweiger, A.; Flanagan, M. E.; Gloger, A.; Hansen, N. J. V.; Kuai, L.; Kunig, V. B. K.; Lu, X.; Madsen, D.; Marcaurelle, L. A.; Mulrooney, C.; O’Donovan, G.; Sakata, S.; Scheuermann, J. DNA-encoded chemical libraries. Nature Reviews Methods Primers 2022, 2 (1). https://doi.org/10.1038/s43586-021-00084-5.
  4. Mannocci, L.; Zhang, Y.; Scheuermann, J.; Leimbacher, M.; De Bellis, G.; Rizzi, E.; Dumelin, C.; Melkko, S.; Neri, D. High-throughput sequencing allows the identification of binding molecules isolated from DNA-encoded chemical libraries. Proc. Natl. Acad. Sci. U. S. A. 2008, 105 (46), 17670-5. https://doi.org/10.1073/pnas.0805130105.
    |
  5. Liu, R.; Li, X.; Lam, K. S. Combinatorial chemistry in drug discovery. Curr. Opin. Chem. Biol. 2017, 38, 117-126. https://doi.org/10.1016/j.cbpa.2017.03.017.
    |
  6. Deng, H.; O'Keefe, H.; Davie, C. P.; Lind, K. E.; Acharya, R. A.; Franklin, G. J.; Larkin, J.; Matico, R.; Neeb, M.; Thompson, M. M.; Lohr, T.; Gross, J. W.; Centrella, P. A.; O'Donovan, G. K.; Bedard, K. L.; van Vloten, K.; Mataruse, S.; Skinner, S. R.; Belyanskaya, S. L.; Carpenter, T. Y.; Shearer, T. W.; Clark, M. A.; Cuozzo, J. W.; Arico-Muendel, C. C.; Morgan, B. A. Discovery of highly potent and selective small molecule ADAMTS-5 inhibitors that inhibit human cartilage degradation via encoded library technology (ELT). J. Med. Chem. 2012, 55 (16), 7061-79. https://doi.org/10.1021/jm300449x.
    |
  7. Madsen, D.; Azevedo, C.; Micco, I.; Petersen, L. K.; Hansen, N. J. V. An overview of DNA-encoded libraries: A versatile tool for drug discovery. Prog. Med. Chem. 2020, 59, 181-249. https://doi.org/10.1016/bs.pmch.2020.03.001.
    |
  8. Petersen, L. K.; Christensen, A. B.; Andersen, J.; Folkesson, C. G.; Kristensen, O.; Andersen, C.; Alzu, A.; Slok, F. A.; Blakskjaer, P.; Madsen, D.; Azevedo, C.; Micco, I.; Hansen, N. J. V. Screening of DNA-Encoded Small Molecule Libraries inside a Living Cell. J. Am. Chem. Soc. 2021, 143 (7), 2751-2756. https://doi.org/10.1021/jacs.0c09213.
    |
  9. Satz, A. L.; Kuai, L.; Peng, X. Selections and screenings of DNA-encoded chemical libraries against enzyme and cellular targets. Bioorg. Med. Chem. Lett. 2021, 39, 127851. https://doi.org/10.1016/j.bmcl.2021.127851.
    |
  10. Huang, Y.; Li, Y.; Li, X. Strategies for developing DNA-encoded libraries beyond binding assays. Nat. Chem. 2022, 14 (2), 129-140. https://doi.org/10.1038/s41557-021-00877-x.
    |
  11. Roy, A.; Kodadek, T. DELs Inside Cells. Trends in Pharmacological Sciences 2020, 41 (4), 225-227. https://doi.org/10.1016/j.tips.2020.01.007.
    |
  12. Bassi, G.; Favalli, N.; Oehler, S.; Martinelli, A.; Catalano, M.; Scheuermann, J.; Neri, D. Comparative evaluation of DNA-encoded chemical selections performed using DNA in single-stranded or double-stranded format. Biochem. Biophys. Res. Commun. 2020, 533 (2), 223-229. https://doi.org/10.1016/j.bbrc.2020.04.035.
    |
  13. Li, X.; Liu, D. R. DNA-templated organic synthesis: nature's strategy for controlling chemical reactivity applied to synthetic molecules. Angew. Chem. Int. Ed. Engl. 2004, 43 (37), 4848-70. https://doi.org/10.1002/anie.200400656.
    |
  14. Fair, R. J.; Walsh, R. T.; Hupp, C. D. The expanding reaction toolkit for DNA-encoded libraries. Bioorg. Med. Chem. Lett. 2021, 51, 128339. https://doi.org/10.1016/j.bmcl.2021.128339.
    |
  15. Clark, M. A.; Acharya, R. A.; Arico-Muendel, C. C.; Belyanskaya, S. L.; Benjamin, D. R.; Carlson, N. R.; Centrella, P. A.; Chiu, C. H.; Creaser, S. P.; Cuozzo, J. W.; Davie, C. P.; Ding, Y.; Franklin, G. J.; Franzen, K. D.; Gefter, M. L.; Hale, S. P.; Hansen, N. J.; Israel, D. I.; Jiang, J.; Kavarana, M. J.; Kelley, M. S.; Kollmann, C. S.; Li, F.; Lind, K.; Mataruse, S.; Medeiros, P. F.; Messer, J. A.; Myers, P.; O'Keefe, H.; Oliff, M. C.; Rise, C. E.; Satz, A. L.; Skinner, S. R.; Svendsen, J. L.; Tang, L.; van Vloten, K.; Wagner, R. W.; Yao, G.; Zhao, B.; Morgan, B. A. Design, synthesis and selection of DNA-encoded small-molecule libraries. Nat. Chem. Biol. 2009, 5 (9), 647-54. https://doi.org/10.1038/nchembio.211.
    |
  16. Gerry, C. J.; Wawer, M. J.; Clemons, P. A.; Schreiber, S. L. DNA Barcoding a Complete Matrix of Stereoisomeric Small Molecules. J. Am. Chem. Soc. 2019, 141 (26), 10225-10235. https://doi.org/10.1021/jacs.9b01203.
    |
  17. Fitzgerald, P. R.; Paegel, B. M. DNA-Encoded Chemistry: Drug Discovery from a Few Good Reactions. Chem. Rev. 2021, 121 (12), 7155-7177. https://doi.org/10.1021/acs.chemrev.0c00789.
    |
  18. Song, M.; Hwang, G. T. DNA-Encoded Library Screening as Core Platform Technology in Drug Discovery: Its Synthetic Method Development and Applications in DEL Synthesis. J. Med. Chem. 2020, 63 (13), 6578-6599. https://doi.org/10.1021/acs.jmedchem.9b01782.
    |
  19. Pikalyova, R.; Zabolotna, Y.; Volochnyuk, D. M.; Horvath, D.; Marcou, G.; Varnek, A. Exploration of the Chemical Space of DNA‐encoded Libraries. Molecular Informatics 2022, 41 (6). https://doi.org/10.1002/minf.202100289.
    |
  20. Shi, B.; Zhou, Y.; Huang, Y.; Zhang, J.; Li, X. Recent advances on the encoding and selection methods of DNA-encoded chemical library. Bioorg. Med. Chem. Lett. 2017, 27 (3), 361-369. https://doi.org/10.1016/j.bmcl.2016.12.025.
    |
  21. Salamon, H.; Klika Skopic, M.; Jung, K.; Bugain, O.; Brunschweiger, A. Chemical Biology Probes from Advanced DNA-encoded Libraries. ACS Chem. Biol. 2016, 11 (2), 296-307. https://doi.org/10.1021/acschembio.5b00981.
    |
  22. Zhu, H.; Foley, T. L.; Montgomery, J. I.; Stanton, R. V. Understanding Data Noise and Uncertainty through Analysis of Replicate Samples in DNA-Encoded Library Selection. J. Chem. Inf. Model. 2022, 62 (9), 2239-2247. https://doi.org/10.1021/acs.jcim.1c00986.
    |
  23. Foley, T. L.; Burchett, W.; Chen, Q.; Flanagan, M. E.; Kapinos, B.; Li, X.; Montgomery, J. I.; Ratnayake, A. S.; Zhu, H.; Peakman, M. C. Selecting Approaches for Hit Identification and Increasing Options by Building the Efficient Discovery of Actionable Chemical Matter from DNA-Encoded Libraries. SLAS Discov. 2021, 26 (2), 263-280. https://doi.org/10.1177/2472555220979589.
    |
  24. Needels, M. C.; Jones, D. G.; Tate, E. H.; Heinkel, G. L.; Kochersperger, L. M.; Dower, W. J.; Barrett, R. W.; Gallop, M. A. Generation and screening of an oligonucleotide-encoded synthetic peptide library. Proc. Natl. Acad. Sci. U. S. A. 1993, 90 (22), 10700-4. https://doi.org/10.1073/pnas.90.22.10700.
    |
  25. de Pedro Beato, E.; Priego, J.; Gironda-Martinez, A.; Gonzalez, F.; Benavides, J.; Blas, J.; Martin-Ortega, M. D.; Toledo, M. A.; Ezquerra, J.; Torrado, A. Mild and Efficient Palladium-Mediated C-N Cross-Coupling Reaction between DNA-Conjugated Aryl Bromides and Aromatic Amines. ACS Comb. Sci. 2019, 21 (2), 69-74. https://doi.org/10.1021/acscombsci.8b00142.
    |
  26. Monty, O. B. C.; Nyshadham, P.; Bohren, K. M.; Palaniappan, M.; Matzuk, M. M.; Young, D. W.; Simmons, N. Homogeneous and Functional Group Tolerant Ring-Closing Metathesis for DNA-Encoded Chemical Libraries. ACS Comb. Sci. 2020, 22 (2), 80-88. https://doi.org/10.1021/acscombsci.9b00199.
    |
  27. Lu, X.; Fan, L.; Phelps, C. B.; Davie, C. P.; Donahue, C. P. Ruthenium Promoted On-DNA Ring-Closing Metathesis and Cross-Metathesis. Bioconjug. Chem. 2017, 28 (6), 1625-1629. https://doi.org/10.1021/acs.bioconjchem.7b00292.
    |
  28. Devaraj, N. K.; Finn, M. G. Introduction: Click Chemistry. Chem. Rev. 2021, 121 (12), 6697-6698. https://doi.org/10.1021/acs.chemrev.1c00469.
    |
  29. Reddavide, F. V.; Lin, W.; Lehnert, S.; Zhang, Y. DNA-Encoded Dynamic Combinatorial Chemical Libraries. Angew. Chem. Int. Ed. Engl. 2015, 54 (27), 7924-8. https://doi.org/10.1002/anie.201501775.
    |
  30. An, Y.; Yan, H.; Dong, Z.; Satz, A. L. DNA-Compatible Click Reaction Employing In Situ Generated Azides from Boronic Acids. Curr. Protoc. 2021, 1 (5), e125. https://doi.org/10.1002/cpz1.125.
    |
  31. Qu, Y.; Wen, H.; Ge, R.; Xu, Y.; Gao, H.; Shi, X.; Wang, J.; Cui, W.; Su, W.; Yang, H.; Kuai, L.; Satz, A. L.; Peng, X. Copper-Mediated DNA-Compatible One-Pot Click Reactions of Alkynes with Aryl Borates and TMS-N(3). Org. Lett. 2020, 22 (11), 4146-4150. https://doi.org/10.1021/acs.orglett.0c01219.
    |
  32. Li, H.; Sun, Z.; Wu, W.; Wang, X.; Zhang, M.; Lu, X.; Zhong, W.; Dai, D. Inverse-Electron-Demand Diels-Alder Reactions for the Synthesis of Pyridazines on DNA. Org. Lett. 2018, 20 (22), 7186-7191. https://doi.org/10.1021/acs.orglett.8b03114.
    |
  33. Sun, H.; Xue, Q.; Zhang, C.; Wu, H.; Feng, P. Derivatization based on tetrazine scaffolds: synthesis of tetrazine derivatives and their biomedical applications. Organic Chemistry Frontiers 2022, 9 (2), 481-498. https://doi.org/10.1039/d1qo01324f.
  34. Matsuo, B.; Granados, A.; Levitre, G.; Molander, G. A. Photochemical Methods Applied to DNA Encoded Library (DEL) Synthesis. Acc. Chem. Res. 2023, 56 (3), 385-401. https://doi.org/10.1021/acs.accounts.2c00778.
    |
  35. Martín, A.; Nicolaou, C. A.; Toledo, M. A. Navigating the DNA encoded libraries chemical space. Communications Chemistry 2020, 3 (1). https://doi.org/10.1038/s42004-020-00374-1.
  36. Conole, D.; Hunter, J. H.; Waring, M. J. The maturation of DNA encoded libraries: opportunities for new users. Future Med. Chem. 2021, 13 (2), 173-191. https://doi.org/10.4155/fmc-2020-0285.
    |
  37. Pereira, D. A.; Williams, J. A. Origin and evolution of high throughput screening. Br. J. Pharmacol. 2007, 152 (1), 53-61. https://doi.org/10.1038/sj.bjp.0707373.
    |
  38. Volochnyuk, D. M.; Ryabukhin, S. V.; Moroz, Y. S.; Savych, O.; Chuprina, A.; Horvath, D.; Zabolotna, Y.; Varnek, A.; Judd, D. B. Evolution of commercially available compounds for HTS. Drug Discov. Today 2019, 24 (2), 390-402. https://doi.org/10.1016/j.drudis.2018.10.016.
    |
  39. Buskes, M. J.; Blanco, M. J. Impact of Cross-Coupling Reactions in Drug Discovery and Development. Molecules 2020, 25 (15). https://doi.org/10.3390/molecules25153493.
    |
  40. Shi, Y.; Wu, Y. R.; Yu, J. Q.; Zhang, W. N.; Zhuang, C. L. DNA-encoded libraries (DELs): a review of on-DNA chemistries and their output. RSC Adv. 2021, 11 (4), 2359-2376. https://doi.org/10.1039/d0ra09889b.
  41. Zabolotna, Y.; Volochnyuk, D. M.; Ryabukhin, S. V.; Gavrylenko, K.; Horvath, D.; Klimchuk, O.; Oksiuta, O.; Marcou, G.; Varnek, A. SynthI: A New Open-Source Tool for Synthon-Based Library Design. J. Chem. Inf. Model. 2022, 62 (9), 2151-2163. https://doi.org/10.1021/acs.jcim.1c00754.
    |
  42. Zabolotna, Y.; Volochnyuk, D. M.; Ryabukhin, S. V.; Horvath, D.; Gavrilenko, K. S.; Marcou, G.; Moroz, Y. S.; Oksiuta, O.; Varnek, A. A Close-up Look at the Chemical Space of Commercially Available Building Blocks for Medicinal Chemistry. J. Chem. Inf. Model. 2022, 62 (9), 2171-2185. https://doi.org/10.1021/acs.jcim.1c00811.
    |
  43. Verma, A.; Ram Yadav, M.; Giridhar, R.; Prajapati, N.; C. Tripathi, A.; K. Saraf, S. Nitrogen Containing Privileged Structures and their Solid Phase Combinatorial Synthesis. Combinatorial Chemistry & High Throughput Screening 2013, 16 (5), 345-393. http://dx.doi.org/10.2174/1386207311316050003.
    |
  44. Mishra, B. B.; Kumar, D.; Mishra, A.; Mohapatra, P. P.; Tiwari, V. K., Chapter 2 - Cyclo-Release Strategy in Solid-Phase Combinatorial Synthesis of Heterocyclic Skeletons. In Advances in Heterocyclic Chemistry, Katritzky, A. R., Ed. Academic Press: 2012; Vol. 107, pp 41-99. https://doi.org/10.1016/B978-0-12-396532-5.00002-0.
  45. Kunig, V. B. K.; Ehrt, C.; Domling, A.; Brunschweiger, A. Isocyanide Multicomponent Reactions on Solid-Phase-Coupled DNA Oligonucleotides for Encoded Library Synthesis. Org. Lett. 2019, 21 (18), 7238-7243. https://doi.org/10.1021/acs.orglett.9b02448.
    |
  46. Du, H. C.; Bangs, M. C.; Simmons, N.; Matzuk, M. M. Multistep Synthesis of 1,2,4-Oxadiazoles via DNA-Conjugated Aryl Nitrile Substrates. Bioconjug. Chem. 2019, 30 (5), 1304-1308. https://doi.org/10.1021/acs.bioconjchem.9b00188.
    |
  47. Potewar, T. M.; Ingale, S. A.; Srinivasan, K. V. Catalyst-free efficient synthesis of 2-aminothiazoles in water at ambient temperature. Tetrahedron 2008, 64 (22), 5019-5022. https://doi.org/10.1016/j.tet.2008.03.082.
  48. Shaaban, S.; Abdel-Wahab, B. F. Groebke-Blackburn-Bienayme multicomponent reaction: emerging chemistry for drug discovery. Mol. Divers. 2016, 20 (1), 233-54. https://doi.org/10.1007/s11030-015-9602-6.
    |
  49. Satz, A. L.; Cai, J.; Chen, Y.; Goodnow, R.; Gruber, F.; Kowalczyk, A.; Petersen, A.; Naderi-Oboodi, G.; Orzechowski, L.; Strebel, Q. DNA Compatible Multistep Synthesis and Applications to DNA Encoded Libraries. Bioconjug. Chem. 2015, 26 (8), 1623-32. https://doi.org/10.1021/acs.bioconjchem.5b00239.
    |
  50. Kolmel, D. K.; Ratnayake, A. S.; Flanagan, M. E.; Tsai, M. H.; Duan, C.; Song, C. Photocatalytic [2+2] Cycloaddition in DNA-Encoded Chemistry. Org. Lett. 2020, 22 (8), 2908-2913. https://doi.org/10.1021/acs.orglett.0c00574.
    |
  51. Potowski, M.; Kunig, V. B. K.; Losch, F.; Brunschweiger, A. Synthesis of DNA-coupled isoquinolones and pyrrolidines by solid phase ytterbium- and silver-mediated imine chemistry. MedChemComm 2019, 10 (7), 1082-1093. https://doi.org/10.1039/c9md00042a.
  52. Fan, L.; Davie, C. P. Zirconium(IV)-Catalyzed Ring Opening of on-DNA Epoxides in Water. Chembiochem 2017, 18 (9), 843-847. https://doi.org/10.1002/cbic.201600563.
    |
  53. Wu, W.; Sun, Z.; Wang, X.; Lu, X.; Dai, D. Construction of Thiazole-Fused Dihydropyrans via Formal [4+2] Cycloaddition Reaction on DNA. Org. Lett. 2020, 22 (8), 3239-3244. https://doi.org/10.1021/acs.orglett.0c01016.
    |
  54. Tian, X.; Basarab, G. S.; Selmi, N.; Kogej, T.; Zhang, Y.; Clark, M.; Goodnow Jr, R. A. Development and design of the tertiary amino effect reaction for DNA-encoded library synthesis. MedChemComm 2016, 7 (7), 1316-1322. https://doi.org/10.1039/c6md00088f.
  55. Li, K.; Liu, X.; Liu, S.; An, Y.; Shen, Y.; Sun, Q.; Shi, X.; Su, W.; Cui, W.; Duan, Z.; Kuai, L.; Yang, H.; Satz, A. L.; Chen, K.; Jiang, H.; Zheng, M.; Peng, X.; Lu, X. Solution-Phase DNA-Compatible Pictet-Spengler Reaction Aided by Machine Learning Building Block Filtering. iScience 2020, 23 (6), 101142. https://doi.org/10.1016/j.isci.2020.101142.
  56. Skopic, M. K.; Gotte, K.; Gramse, C.; Dieter, M.; Pospich, S.; Raunser, S.; Weberskirch, R.; Brunschweiger, A. Micellar Bronsted Acid Mediated Synthesis of DNA-Tagged Heterocycles. J. Am. Chem. Soc. 2019, 141 (26), 10546-10555. https://doi.org/10.1021/jacs.9b05696.
    |
  57. Gerry, C. J.; Yang, Z.; Stasi, M.; Schreiber, S. L. DNA-Compatible [3+2] Nitrone-Olefin Cycloaddition Suitable for DEL Syntheses. Org. Lett. 2019, 21 (5), 1325-1330. https://doi.org/10.1021/acs.orglett.9b00017.
    |
  58. Klika Skopic, M.; Willems, S.; Wagner, B.; Schieven, J.; Krause, N.; Brunschweiger, A. Exploration of a Au(I)-mediated three-component reaction for the synthesis of DNA-tagged highly substituted spiroheterocycles. Org. Biomol. Chem. 2017, 15 (40), 8648-8654. https://doi.org/10.1039/c7ob02347b.

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2023-06-03

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(1)
Oksiuta, O. V.; Pashenko, A. E.; Smalii, R. V. .; Volochnyuk, D. M.; Ryabukhin, S. V. Heterocyclization Vs Coupling Reactions: A DNA-Encoded Libraries Case. J. Org. Pharm. Chem. 2023, 21, 3-19.

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Vol. 21 No. 1 (2023)

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Advanced Researches

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