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DOI: 10.1055/a-2079-9310
Chemical Diversification of Carbocyclic Fluorinated Pyrimidine Nucleosides: Introducing 2′-Arabino Analogues and Ring Unsaturation
Keele University, Riboscience LLC, and the Royal Society of Chemistry (Research Enablement Grant E21-7055928079) are thanked for funding to C.M.M.B. UK Research and Innovation (UKRI, Future Leaders Fellowship, MR/T019522/1) are thanked for project grant funding to G.J.M.
Abstract
Analogues of the canonical nucleosides have a longstanding presence and proven capability within medicinal chemistry and drug-discovery research. Herein, we report chemical diversification of carbocyclic pyrimidine nucleosides containing CF2 and CHF in place of the furanose oxygen to introduce ring unsaturation and 2′-epimers. Utilizing gram-scale access to 6′-(R)-monofluoro- and 6′-gem-difluorouridine, we explore the provision of 2′,3′-didehydro-2′,3′-dideoxy, and 1′,2′-didehydro-2′-deoxy analogues, alongside the first example of a 6′-(R)-fluoro arabino-carbauridine. Key stereochemistries and the presence of unsaturation are confirmed using X-ray crystallography and NMR, and an indicative conformational preference for a monofluoro 2′,3′-didehydro-2′,3′-dideoxy system is presented. This synthetic blueprint offers a potential to explore biological activity for these hitherto unavailable materials, including a direct comparison to established nucleoside analogue drugs.
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/a-2079-9310.
- Supporting Information
Publication History
Received: 22 March 2023
Accepted after revision: 24 April 2023
Accepted Manuscript online:
24 April 2023
Article published online:
31 May 2023
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References
- 1 Jordheim LP, Durantel D, Zoulim F, Dumontet C. Nat. Rev. Drug Discovery 2013; 12: 447
- 2 Guinan M, Benckendorff C, Smith M, Miller GJ. Molecules 2020; 25: 2050
- 3 Kulkarni JA, Witzigmann D, Thomson SB, Chen S, Leavitt BR, Cullis PR, van der Meel R. Nat. Nanotechnol. 2021; 16: 630
- 4 van Giesen KJ. D, Thompson MJ, Meng Q, Lovelock SL. JACS Au 2023; 1: 13
- 5 Kaur SP, Gupta V. Virus Res. 2020; 288: 198114
- 6 Eastman RT, Roth JS, Brimacombe KR, Simeonov A, Shen M, Patnaik S, Hall MD. ACS Cent. Sci. 2020; 6: 672
- 7 Syed YY. Drugs 2022; 82: 455
- 8 Miller GJ. Science 2020; 369: 623
- 9 Cosgrove SC, Miller GJ. Expert Opin. Drug Discovery 2022; 17: 355
- 10 Blackburn GM, England DA, Kolkmann F. J. Chem. Soc., Chem. Commun. 1981; 930
- 11 Marquez VE. Adv. Antiviral Drug Des. 1996; 2: 89
- 12 Kálmán A, Yoritsánszky T, Bùres J, Sagi G. Nucleosides Nucleotides 1990; 9: 235
- 13 Kishi T, Muroi M, Kusaka T, Nishikawa M, Kamiya K, Mizuno K. Chem. Pharm. Bull. 1972; 20: 940
- 14 Derudas M, Meneghesso S. In Fluorinated Pharmaceuticals: Advances in Medicinal Chemistry . Westwell AD. Future Science; London: 2015: 30
- 15 Reddy P. Organofluorine Compounds in Biology and Medicine. Elsevier; Amsterdam: 2015: 1
- 16 Pal S, Chandra G, Patel S, Singh S. Chem. Rec. 2022; 22: e202100335
- 17 Shet H, Sahu R, Sanghvi YS, Kapdi AR. Chem. Rec. 2022; 22: e202200066
- 18 Huonnic K, Linclau B. Chem. Rev. 2022; 122: 15503
- 19 Biggadike K, Borthwick AD, Exall AM, Kirk BE, Roberts SM, Youds P, Slawin AM. Z, Williams DJ. J. Chem. Soc., Chem. Commun. 1987; 255
- 20 Madhavan GV, McGee DP, Rydzewski RM, Boehme R, Martin JC, Prisbe EJ. J. Med. Chem. 1988; 31: 1798
- 21 Borthwick AD, Evans DN, Kirk BE, Biggadike K, Exall AM, Youds P, Roberts SM, Knight DJ, Coates JA. V. J. Med. Chem. 1990; 33: 179
- 22 Yang Y.-Y, Meng W.-D, Qing F.-L. Org. Lett. 2004; 6: 4257
- 23 Kumamoto H, Haraguchi K, Ida M, Nakamura KT, Kitagawa Y, Hamasaki T, Baba M, Matsubayashi SS, Tanaka H. Tetrahedron 2009; 65: 7630
- 24 Yoon J.-s, Kim G, Jarhad DB, Kim H.-R, Shin Y.-S, Qu S, Sahu PK, Kim HO, Lee HW. S. Wang B, Kong YJ, Chang T.-S, Ogando NS, Kovacikova K, Snijder EJ, Posthuma CC, van Hemert MJ, Jeong LS. J. Med. Chem. 2019; 62: 6346
- 25 Shin YS, Jarhad DB, Jang MH, Kovacikova K, Kim GJ. Yoon J.-s, Kim H.-R, Hyun YE, Tipnis AS, Chang T.-S. van Hemert M. J., Jeong L. S. 2020; 187: 111956
- 26 Jeong LS, Zhao LX, Choi WJ, Pal S, Park YH, Lee SK, Chun MW, Lee YB, Ahn CH, Moon HR. Nucleosides Nucleotides Nucleic Acids 2007; 26: 713
- 27 Benckendorff CM. M, Slyusarchuk VD, Huang N, Lima MA, Smith M, Miller GJ. Org. Biomol. Chem. 2022; 20: 9469
- 28 Corey EJ, Winter RA. E. J. Am. Chem. Soc. 1963; 85: 2677
- 29 Corey EJ, Carey FA, Winter R. J. Am. Chem. Soc. 1965; 87: 934
- 30 CCDC 2241749 and 2241750 contain the supplementary crystallographic data for compounds 5 and 20. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
- 31 Crank G, Eastwood FW. Aust. J. Chem. 1964; 17: 1392
- 32 Guinan M, Huang N, Hawes CS, Lima MA, Smith M, Miller GJ. Org. Biomol. Chem. 2022; 20: 1401
- 33 Guinan M, Huang N, Smith M, Miller GJ. Bioorg. Med. Chem. Lett. 2022; 61: 128605
- 34 Barton DH. R, McCombie SW. J. Chem. Soc., Perkin Trans. 1 1975; 1574
- 35 Robins MJ, Trip EM. Tetrahedron Lett. 1974; 15: 3369
- 36 Fraser A, Wheeler P, Cook DP, Sanghvi YS. J. Heterocycl. Chem. 1993; 30: 1277
- 37 Robins MJ, Jones RA, Mengel R. J. Am. Chem. Soc. 1976; 98: 8213
- 38 Saebø S, Cordell FR, Boggs JE. J. Mol. Struct.: THEOCHEM 1983; 104: 221
- 39 Leong MK, Mastryukov VS, Boggs JE. J. Mol. Struct. 1998; 445: 149