A Divergent Approach for the Synthesis of d- and l-4′-Ethynyl Dioxolane Nucleosides with Potent Anti-HIV Activity

^§ These authors contributed equally to this work.

Abstract

Novel 4′-C-ethynyl isomeric dioxolane nucleoside analogues (β-d, α-d, β-l, and α-l, respectively) are successfully synthesized via a divergent strategy from the common starting material, (Z)-but-2-ene-1,4-diol, and are characterized and evaluated for their anti-HIV-1 and anti-HIV-2 activities. The β-d and β-l products display potent in vitro activities against HIV-1 (IIIB) with EC₅₀ values of 0.75 and 0.87 μM, respectively, and against HIV-2 (ROD) with EC₅₀ values of 0.75 and 0.35 μM, respectively, being better in comparison with 3TC [EC₅₀, 5.27 μM (HIV-1) and 1.30 μM (HIV-2)]. The β-d and β-l nucleosides also potently inhibit different drug-resistant strains of the HIV-1 virus (L100I, K103N, Y181C, and V106A). The selectivity indices and cytotoxic profiles of the β-d and β-l nucleosides are much better than those of the standard drugs AZT and d4T.

Key words

anti-HIV - AIDS - dioxolane nucleosides - 4′-acetylene nucleosides - divergent synthesis - asymmetric synthesis

• References

• 1a Jung M, Lee S, Kim H. Curr. Med. Chem. 2000; 7: 649
• 1b Muenchhoff M, Prendergast AJ, Goulder PJ. R. Front. Immunol. 2014; 5: 1
• 1c De Clerq E. J. Med. Chem. 2005; 48: 1297
• 2 WHO report 2014 on HIV, see: http://www.who.int/gho/hiv/en/.
• 3 For details, see: https://aidsinfo.nih.gov/education-materials/ fact-sheets/21/58/fda-approved-hiv-medicines.
• 4 Zhan P, Pannecouque C, De Clercq E, Liu X. J. Med. Chem. 2016; 59: 2849
• 5 Chung J, DiGiusto DL, Rossi JJ. Expert Opin. Biol. Ther. 2013; 13: 437
• 6 Huang B, Kang D, Zhan P, Liu X. Expert Opin. Drug Discovery 2015; 10: 1271
• 7a Sari O, Roy V, Balzarini J, Snoeck R, Andrei G, Agrofoglio LA. Eur. J. Med. Chem. 2012; 53: 220
• 7b Ohrui H. Proc. Jpn. Acad., Ser. B 2011; 87: 53
• 7c Haraguchi K, Shimada H, Kimura K, Akutsu G, Tanaka H, Abe H, Hamasaki T, Baba M, Gullen EA, Dutschman GE, Cheng Y.-C, Balzarin J. ACS Med. Chem. Lett. 2011; 2: 692
• 7d Wanga Q, Li Y, Song C, Qian K, Chen C.-H, Lee K.-H, Chang J. Bioorg. Med. Chem. Lett. 2010; 20: 4053
• 7e Haraguchi K, Takeda S, Tanaka H, Nitanda T, Baba M, Dutschman GE, Cheng Y.-C. Bioorg. Med. Chem. Lett. 2003; 13: 3775
• 7f Ohrui H, Kohgo S, Kitano K, Sakata S, Kodama E, Yoshimura K, Matsuoka M, Shigeta S, Mitsuya H. J. Med. Chem. 2000; 43: 4516
• 8a Bondada L, Detorio M, Bassit L, Tao S, Montero CM, Singletary TM, Zhang H, Zhou L, Cho J.-H, Coats SJ, Schinazi RF. ACS Med. Chem. Lett. 2013; 4: 747
• 8b Kim E, Liu LJ, Lee W, Hong JH. Nucleosides, Nucleotides Nucleic Acids 2012; 31: 85
• 8c Bera S, Malik L, Bhat B, Carroll SS, MacCoss M, Olsen DB, Tomassini JE, Eldrup AB. Bioorg. Med. Chem. Lett. 2003; 13: 4455
• 8d Luo M.-Z, Liu M.-C, Mozdziesz DE, Lin T.-S, Dutschman GE, Gullen EA, Cheng Y.-C, Sartorelli AC. Bioorg. Med. Chem. Lett. 2000; 10: 2145
• 8e Kim HO, Ahn SK, Alves AJ, Beach JW, Jeong LS, Choi BG, Roey PV, Schinazi RF, Chu CK. J. Med. Chem. 1992; 35: 1987
• 9a Caso MF, D’Alonzo D, D’Errico S, Palumbo G, Guaragna A. Org. Lett. 2015; 17: 2626
• 9b Marcuccio SM, Epa R, White JM, Deadman JJ. Org. Process Res. Dev. 2011; 15: 763
• 9c Nguyen-Ba N, Lee N, Chan L, Zacharie B. Bioorg. Med. Chem. Lett. 2000; 10: 2223
• 9d Romeo G, Chiacchio U, Corsaro A, Merino P. Chem. Rev. 2010; 110: 3337
• 10 Mosmann T. J. Immunol. Methods 1983; 65: 55
• 11 Pauwels R, Balzarini J, Baba M, Snoeck R, Schols D, Herdewijin P, Desmyter J, De Clercq E. J. Virol. Methods 1998; 121: 309
• 12a Zhang Q, Qu Y, Chen W, Wang Y, Wu Q. Lett. Org. Chem. 2006; 3: 271
• 12b Leftheris K, Goodman M. J. Med. Chem 1990; 33: 216