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Synthesis of water-soluble prodrugs of 5-modified 2ʹ-deoxyuridines and their antibacterial activity

The Journal of Antibiotics volume 73, pages 236–246 (2020)Cite this article

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Abstract

Recently we have synthesized a set of pyrimidine nucleoside derivatives bearing extended alkyltriazolylmethyl substituents at position 5 of the nucleic base, and showed their significant activity against Mycobacterium tuberculosis virulent laboratory strain H37Rv as well as drug-resistant MS-115 strain. The presence of a lengthy hydrophobic substituent leads to the reduction of nucleoside water solubility making their antibacterial activity troublesome to study. A series of water-soluble forms of 5-modified 2ʹ-deoxyuridines 4a–c and 8a–c were synthesized. They appeared at least two orders more soluble compared with the parent compounds 1a and 1b. Their half-hydrolysis time was 5–12 h, which can be considered optimal for prodrugs used in clinics. Obtained compounds showed moderate activity (MIC 48–95 µg·ml−1) against some Gram-positive bacteria including resistant strains of Staphylococcus aureus and Mycobacterium smegmatis and were low cytotoxic for human cell lines (CD50 >> 100 µg·ml−1).

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Acknowledgements

The synthesis and the cytotoxicity studies were supported by the Russian Foundation for Basic Research (RFBR, projects 17-04-00536, 17-00-00395, 17-00-00393 and 18-29-08010). The physicochemical analysis of all compounds was supported the Program of fundamental research for state academies for 2013–2020 years (No. 01201363818). The authors are grateful to Dr R.A. Novikov (Engelhardt Institute of Molecular Biology RAS) for NMR investigations.

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Authors and Affiliations

  1. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilova St., 119991, Moscow, Russia

    Sergey D. Negrya, Maxim V. Jasko, Pavel N. Solyev, Inna L. Karpenko, Sergey N. Kochetkov & Liudmila A. Alexandrova

  2. Gause Institute of New Antibiotics, 11 Bolshaya Pirogovskaya St., 119021, Moscow, Russia

    Olga V. Efremenkova, Byazilya F. Vasilyeva & Irina G. Sumarukova

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  1. Sergey D. Negrya
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  2. Maxim V. Jasko
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Correspondence to Liudmila A. Alexandrova.

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Negrya, S.D., Jasko, M.V., Solyev, P.N. et al. Synthesis of water-soluble prodrugs of 5-modified 2ʹ-deoxyuridines and their antibacterial activity. J Antibiot 73, 236–246 (2020). https://doi.org/10.1038/s41429-019-0273-x

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