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Triphenylphosphonium conjugates of 1,2,3-triazolyl nucleoside analogues. Synthesis and cytotoxicity evaluation

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Abstract

A series of triphenylphosphonium (TPP) conjugates of 1,2,3-triazolyl analogues of several pyrimidine nucleosides was synthesized and evaluated for the in vitro cytotoxicity against human cancer cell lines M-HeLa, MCF-7, PANC-1, PC-3, DU145, SKOV-3, A275, and normal human cell line WI-38. In these TPP-conjugates triphenylphosphonium cation was attached via a tetramethylene chain to the N-3 atom of the heterocycle moiety (uracil, thymine, quinazoline-2,4-dione), which was coupled with the D-ribofuranosyl-1,2,3-triazol-4-yl fragment via methylene or tetramethylene linker. It was shown for the first time that the conjugation of 1,2,3-triazolyl derivatives of uridine, its analogues featuring quinazoline-2,4-dione fragment as well as uracil and thymine derivatives, having propargyl or a 1,2,3-triazolyl substituent at the N-1 atom, with a TPP-butyl cation endowed some of them with cytotoxic activity against human cancer cells. Among all human cancer cell lines used, DU-145 and A375 cells were the most sensitive to these TPP conjugates. At the same time, all tested compounds did not inhibit growth of normal cells WI-38. Propargyl containig TPP-conjugates of uracil 4f, 4j, and thymine 5f showed the highest cytotoxicity with IC50 values in the low micromolar concentration range. The present findings suggest that TPP-conjugates of uracil and thymine derivatives would be promising for further development as an anticancer agent.

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Acknowledgements

The authors from Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, RAS are grateful to the Assigned Spectral-Analytical Center of FRC Kazan Scientific Center of RAS for technical assistance in research.

Funding

Synthesis and cytotoxicity evaluation were supported by the Russian Science Foundation (grant no. 19-13-00003). Phenotypic sea urchin embryo assay was performed by MNS under the IDB RAS Government basic research program in 2020 no. 0088-2019-0005. IYS is grateful to the Ministry of Education and Science of the Russian Federation (theme no. AAAA-A18-118040390114-8) for financial support.

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Authors and Affiliations

  1. Arbuzov Institute of Organic and Physical Chemistry, Federal Research Center “Kazan Scientific Center of the Russian Academy of Sciences”, Arbuzov Str., 8, Kazan, 420088, Russian Federation

    Irina Yu. Strobykina, Olga V. Andreeva, Mayya G. Belenok, Anastasiya S. Sapunova, Alexandra D. Voloshina, Alexey B. Dobrynin, Vyacheslav E. Semenov & Vladimir E. Kataev

  2. N. K. Kol’tsov Institute of Developmental Biology, Russian Academy of Sciences, Vavilov Street, 26, Moscow, 119334, Russian Federation

    Marina N. Semenova

  3. N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect, 47, Moscow, 119991, Russian Federation

    Victor V. Semenov

  4. Moscow Institute of Physics and Technology (State University), Institutskiy per. 9, Dolgoprudny, Moscow Region, 141701, Russian Federation

    Roman N. Chuprov-Netochin

Authors
  1. Irina Yu. Strobykina
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  2. Olga V. Andreeva
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  3. Mayya G. Belenok
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  4. Marina N. Semenova
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  8. Alexandra D. Voloshina
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Correspondence to Vyacheslav E. Semenov.

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Strobykina, I.Y., Andreeva, O.V., Belenok, M.G. et al. Triphenylphosphonium conjugates of 1,2,3-triazolyl nucleoside analogues. Synthesis and cytotoxicity evaluation. Med Chem Res 29, 2203–2217 (2020). https://doi.org/10.1007/s00044-020-02629-x

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