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Phosphoramidate conjugates of 3′-azido-3′-deoxythymidine glycerolipid derivatives and amino acid esters: synthesis and anti-HIV activity

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Abstract

We report the synthesis of phosphoramidate conjugates of 3′-azido-3′-deoxythymidine (AZT) glycerolipid derivatives and amino acid esters. For the synthesized compounds, 50% inhibition of the HIV-1 MvP-899 strain in human T lymphoid MT-4 cells is achieved at concentrations of 0.014–0.356 µM. Significantly, compound 3c (which contained ethyl ester of α-alanine) was found to be the most active with EC50 value 0.014 µM. We show that, among these glycerolipid derivatives of AZT, some compounds are less toxic than AZT, and also they possess a similar or higher selectivity index compared to AZT (SI = 11643).

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Abbreviations

AIDS:

Acquired human immunodeficiency syndrome

Ala:

Alanine

AZT:

3′-azido-3′-deoxythymidine

EC50:

Half maximal effective concentration

HAART:

Highly active antiretroviral therapy

HIV:

Human immunodeficiency virus

NMR:

Nuclear magnetic resonance

NRTI:

Nucleoside reverse transcriptase inhibitor

SI:

Selectivity index

TLC:

Thin-layer chromatography

СС50:

Half maximal cytotoxic concentration

References

  1. UNAIDS. Global HIV & AIDS statistics—2020 fact sheet. UNAIDS. 2020. https://www.unaids.org/en/resources/fact-sheet. Accessed 17 Feb 2020.

  2. Gortmaker SL, Hughes M, Cervic J, Brady M, Johnson GM, Seage GR, et al. Pediatric AIDS clinical trials group protocol 219 team. Effect of combination therapy including protease inhibitors on mortality among children and adolescents unfected with HIV-1. NEJM. 2001;345:1522–28. https://doi.org/10.1056/NEJMoa011157.

    Article  CAS  PubMed  Google Scholar 

  3. Gumina G, Choi Y, Chu CK. Recent advances in antiviral nucleosides. Antivir Nucleosides. 2003;1:1–76. https://doi.org/10.1016/B978-044451319-9/50001-4.

    Article  Google Scholar 

  4. Clercq E. Antiviral drug discovery and development: where chemistry meets with biomedicine. Antivir Res. 2005;67:56–75. https://doi.org/10.1016/j.antiviral.2005.05.001.

    Article  PubMed  Google Scholar 

  5. Wong A, Toth I. Lipid, sugar and liposaccharide based delivery systems. Curr Med Chem. 2001;8:1123–36. https://doi.org/10.2174/0929867013372535.

    Article  CAS  PubMed  Google Scholar 

  6. Galegov GA. Phosphazide (nikavir) is a highly effective drug for the treatment of HIV/AIDS infection. Vopr Virusol. 2017;62:5–11. https://doi.org/10.18821/0507-4088-2017-62-1-5-11.

  7. Trznadel R, Singh A, Kleczewska N, Liberska J, Ruszkowski R, Celewicz L. Synthesis and in vitro anticancer activity of new gemcitabine-nucleoside analogue dimers containing methyltriazole or ester-methyltriazole linker. Bioorg Med Chem Lett. 2019;29:2587–94. https://doi.org/10.1016/j.bmcl.2019.08.003.

    Article  CAS  PubMed  Google Scholar 

  8. Seley-Radtke KL, Yates MK. The evolution of nucleoside analogue antivirals: a review for chemists and non-chemists. Part 1: early structural modifications to the nucleoside scaffold. Antivir Res. 2018;154:66–86. https://doi.org/10.1016/j.antiviral.2018.04.004.

    Article  CAS  PubMed  Google Scholar 

  9. Chudinov MV. Ribavirin and its analogs: can you teach an old dog new tricks? Fine Chem Technol 2019;14:7–23. https://doi.org/10.32362/2410-6593-2019-14-4-7-23.

    Article  CAS  Google Scholar 

  10. Llibre JM, Sharon W, Gatell JM. Backbones versus core agents in initial ART regimens: one game, two players. J Antimicrob Chemother. 2016;71:856–61. https://doi.org/10.1093/jac/dkv429.

    Article  CAS  PubMed  Google Scholar 

  11. Yoshio H. Recent progress in prodrug design strategies based on generally applicable modifications. Bioorg Med Chem Lett. 2017;27:1627–32. https://doi.org/10.1016/j.bmcl.2017.02.075.

    Article  Google Scholar 

  12. Smith N, Bade AN, Soni D, Gautam N, Alnouti Y, Herskovitz J, et al. A long acting nanoformulated lamivudine ProTide. Biomater. 2019;223:1–11. https://doi.org/10.1016/j.biomaterials.2019.119476.

    Article  Google Scholar 

  13. Lambert DM. Rationale and applications of lipids as prodrug carriers. Eur J Pharm Sci. 2000;11:15–27. https://doi.org/10.1016/S0928-0987(00)00161-5.

    Article  Google Scholar 

  14. Shastina NS, Maltseva TYU, D’yakova LN, Lobach OA, Chataeva MS, Nosik DN, et al. Synthesis, properties, and anti-HIV activity of new lipophilic 3’-azido-3’-deoxythymidine conjugates containing functional phosphoric linkages. Russ J Bioorg Chem. 2013;39:161–9. https://doi.org/10.1134/S1068162013020118.

    Article  CAS  Google Scholar 

  15. Saboulard D, Naesens L, Cahard D, Salgado A, Pathirana R, Velazquez S, et al. Characterization of the activation pathway of phosphoramidate triester prodrugs of stavudine and zidovudine. Mol Pharm. 1999;56:693–704.

    CAS  Google Scholar 

  16. Mavromoustakos T, Calogeropoulou T, Koufaki M, Kolocouris A, Daliani I, Demetzos C, et al. Ether phospholipid-AZT conjugates possessing anti-HIV and antitumor cell activity. Synthesis, conformation analysis, and study of their thermal effects on membrane bilayer. J Med Chem. 2001;44:1702–9. https://doi.org/10.1021/jm001121c.

    Article  CAS  PubMed  Google Scholar 

  17. Piantadosi C, Marasco C, Morris-Natschke L, Meyer K, Gumus F, Surles J, et al. Synthesis and evalution of novel ether lipid nucleoside conjugates for anti-HIV-1 activity. J Med Chem. 1991;34:1408–14.

    Article  CAS  Google Scholar 

  18. Amyere M, Payrastre B, Krause U, Smissen P, Veithen A, Courtoy PJ. Constitutive macropinocytosis in oncogenetransformed fibroblasts depends on sequential permanent activation of phosphoinositide 3-kinase and phospholipase C. Mol Biol Cell. 2020;11:3453–67. https://doi.org/10.1091/mbc.11.10.3453.

    Article  Google Scholar 

  19. Doherty GJ, McMahon HT. Mechanisms of endocytosis. Annu Rev Biochem. 2009;78:857–902. https://doi.org/10.1146/annurev.biochem.78.081307.110540.

    Article  CAS  PubMed  Google Scholar 

  20. Swanson JA, Hoppe AD. The coordination of signaling during Fc receptor-mediated phagocytosis. J Leukoc Biol. 2004;76:1093–103. https://doi.org/10.1189/jlb.0804439.

    Article  CAS  PubMed  Google Scholar 

  21. Harmon B, Ratner L. Induction of the Gαq signaling cascade by the human immunodeficiency virus envelope is required for virus entry. J Virol. 2008;82:9191–205. https://doi.org/10.1128/JVI.00424-08.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Contreras X, Mzoughi O, Gaston F, Peterlin MB, Bahraoui E. Protein kinase C-delta regulates HIV-1 replication at an early post-entry step in macrophages. Retrovirology. 2012;9:37. https://doi.org/10.1186/1742-4690-9-37.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Xiao Q, Sun J, Ju Y, Zhao Y, Ciu Y. Novel approach to the synthesis of AZT 5‘-O-hydrogen phospholipids. Tetrahedron Lett. 2002;43:5281–3. https://doi.org/10.1016/S0040-4039(02)01045-6.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by the Ministry of Science and Higher Education of the Russian Federation (Project No. 0706-2020-0019).

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Authors and Affiliations

  1. Institute of Fine Chemical Technologies, MIREA—Russian Technological University, Moscow, 119571, Russia

    Elizaveta S. Darnotuk, Nikolay V. Shulga & Natal’ya S. Shastina

  2. Department of Molecular Neuroimmune Signalling, Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia

    Andrei E. Siniavin

  3. N.F. Gamaleya National Research Center for Epidemiology and Microbiology, D.I. Ivanovsky Institute of Virology, Ministry of Health of the Russian Federation, Moscow, 123098, Russia

    Andrei E. Siniavin & Eduard V. Karamov

Authors
  1. Elizaveta S. Darnotuk
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  2. Andrei E. Siniavin
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  5. Natal’ya S. Shastina
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Correspondence to Elizaveta S. Darnotuk.

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Darnotuk, E.S., Siniavin, A.E., Shulga, N.V. et al. Phosphoramidate conjugates of 3′-azido-3′-deoxythymidine glycerolipid derivatives and amino acid esters: synthesis and anti-HIV activity. Med Chem Res 30, 664–671 (2021). https://doi.org/10.1007/s00044-020-02672-8

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