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Abstract <p>Triphenylphosphonium (TPP) conjugates of nucleoterpenoids were synthesized for the first time, and these were nucleoterpenoids consisting of the diterpenoid isosteviol (16-oxo-<i>ent</i>-beyran-19-oic acid) and uracil. In these conjugates, the TPP cation was attached by a polymethylene linker to the <i>N</i><sup>3</sup> atom of the uracil moiety. In turn, the <i>N</i><sup>1</sup> atom of the uracil moiety was bound by a 1,2,3-triazole-4-yl-alkyl (methyl or <i>n</i>-butyl) linker to the 16(<i>S</i>)-position of the isosteviol moiety. The screening of <i>in vitro</i> cytotoxicity of the synthesized TPP-conjugates revealed their high activity (IC<sub>50</sub> = 0.4–15.5 µM) against cancer cells M-HeLa, MCF-7, PANK-1, PC-3, T 98G, A 549, and HuTu 80. The mechanism of the <i>in vitro</i> cytotoxic effect of the lead compound [(1′-{1′′-[19-(ethyloxycarbonyl)-<i>ent</i>-beyeran-16(<i>S</i>)-yl]-1<i>H</i>-1,2,3-triazol-4′′-yl-butyl}-1<i>H</i>,3<i>H</i>-pyrimidine-2,4-dione-3′-yl)decyl]triphenylphosphonium bromide, in which the TPP cation is attached to the nucleoterpenoid fragment by a decyl linker, against M-HeLa cancer cells, was studied by flow cytofluorometry. The results obtained indicated that [(1′-{1′′-[19-(ethyloxycarbonyl)-<i>ent</i>-beyeran-16(<i>S</i>)-yl]-1<i>H</i>-1,2,3-triazol-4′′-yl-butyl}-1<i>H</i>,3<i>H</i>-pyrimidine-2,4-dione-3′-yl)decyl]triphenylphosphonium bromide reduced the mitochondrial membrane potential, induced apoptosis along the mitochondrial pathway and delayed the cell cycle at an early stage G1.</p>

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Triphenylphosphonium Conjugates of Nucleoterpenoids Based on Isosteviol and Uracil. Synthesis and in vitro Cytotoxic Activity

  • 期刊论文

  • 发表日期：

    2026年7月20日

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  • Olga V. Andreeva,
  • Bulat F. Garifullin,
  • Maya G. Belenok,
  • Anna P. Lyubina,
  • Alexandra D. Voloshina,
  • Andrey A. Parfenov,
  • Radmila R. Sharipova,
  • Marina M. Shulaeva,
  • Dinara F. Gumarova,
  • Vyacheslav E. Semenov,
  • Vladimir E. Kataev

摘要

Abstract

Triphenylphosphonium (TPP) conjugates of nucleoterpenoids were synthesized for the first time, and these were nucleoterpenoids consisting of the diterpenoid isosteviol (16-oxo-ent-beyran-19-oic acid) and uracil. In these conjugates, the TPP cation was attached by a polymethylene linker to the N3 atom of the uracil moiety. In turn, the N1 atom of the uracil moiety was bound by a 1,2,3-triazole-4-yl-alkyl (methyl or n-butyl) linker to the 16(S)-position of the isosteviol moiety. The screening of in vitro cytotoxicity of the synthesized TPP-conjugates revealed their high activity (IC50 = 0.4–15.5 µM) against cancer cells M-HeLa, MCF-7, PANK-1, PC-3, T 98G, A 549, and HuTu 80. The mechanism of the in vitro cytotoxic effect of the lead compound [(1′-{1′′-[19-(ethyloxycarbonyl)-ent-beyeran-16(S)-yl]-1H-1,2,3-triazol-4′′-yl-butyl}-1H,3H-pyrimidine-2,4-dione-3′-yl)decyl]triphenylphosphonium bromide, in which the TPP cation is attached to the nucleoterpenoid fragment by a decyl linker, against M-HeLa cancer cells, was studied by flow cytofluorometry. The results obtained indicated that [(1′-{1′′-[19-(ethyloxycarbonyl)-ent-beyeran-16(S)-yl]-1H-1,2,3-triazol-4′′-yl-butyl}-1H,3H-pyrimidine-2,4-dione-3′-yl)decyl]triphenylphosphonium bromide reduced the mitochondrial membrane potential, induced apoptosis along the mitochondrial pathway and delayed the cell cycle at an early stage G1.