Triphenylphosphonium conjugates of 1,2,3-triazolyl nucleoside analogues. Synthesis and cytotoxicity evaluation
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Medicinal Chemistry Research https://doi.org/10.1007/s00044-020-02629-x
ORIGINAL RESEARCH
Triphenylphosphonium conjugates of 1,2,3-triazolyl nucleoside analogues. Synthesis and cytotoxicity evaluation Irina Yu. Strobykina1 Olga V. Andreeva1 Mayya G. Belenok1 Marina N. Semenova2 Victor V. Semenov3 Roman N. Chuprov-Netochin4 Anastasiya S. Sapunova1 Alexandra D. Voloshina1 Alexey B. Dobrynin1 Vyacheslav E. Semenov 1 Vladimir E. Kataev1 ●
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Received: 18 July 2020 / Accepted: 3 September 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
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-2,4dione 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. Keywords Nucleoside analogues 1,2,3-Triazole Triphenylphosphonium TPP conjugates Cytotoxicity ●
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Introduction
Supplementary information The online version of this article (https:// doi.org/10.1007/s00044-020-02629-x) contains supplementary material, which is available to authorized users. * Vyacheslav E. Semenov [email protected] 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
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N. K. Kol’tsov Institute of Developmental Biology, Russian Academy of Sciences, Vavilov Street, 26, Moscow 119334, Russian Federation
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N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect, 47, Moscow 119991, Russian Federation
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Moscow Institute of Physics and Technology (State University), Institutskiy per. 9, Dolgoprudny, Moscow Region 141701, Russian Federation
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