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<p>A set of 3,5-bis(ylidene)-4-piperidone-1-phosphonothioates <b>20a‒l</b> was synthesized in high yields through dehydrochlorination reaction of 3,5-bis(ylidene)-4-piperidones <b>18a‒l</b> and diethyl chlorothiophosphate <b>19</b> in DMF containing quantitative amounts of TEA at 0&#xa0;°C. Most of the synthesized agents exhibit effective antiproliferation properties against a variety of cancer cell lines (MCF7/breast, HCT116/colon, and A431/skin), outperforming the efficacy of the clinically approved drugs. Compound <b>20c</b> (R&#xa0;= 3-ClC<sub>6</sub>H<sub>4</sub>) is the most effective analog discovered with a sub-micromolar activity against MCF7 (IC<sub>50</sub> = 0.650, 3.15 and 3.97 µM, for <b>20c</b>, 5-fluorouracil, and sunitinib, respectively) as well as remarkable efficacy against HCT116, and A431 (IC<sub>50</sub> = 1.445 and 2.920 µM respectively for <b>20c</b>, compared to 20.43 and 23.44 µM respectively for 5-fluorouracil). The synthesized analogs demonstrating considerable anti-MCF7 properties were evaluated for their biochemical properties against MDM2, p53, and topoisomerase I/II. Compound <b>20k</b> [R&#xa0;= 3,4,5-(MeO)<sub>3</sub>C<sub>6</sub>H<sub>2</sub>] is the most effective anti-MDM2 agent with a potency higher than the standard reference (% inhibition of 65.3, for <b>20k</b>, and 42.2 for doxorubicin; i.e. 1.55-fold). Biochemical activation of p53 by the synthesized analogs is consistent with the anti-MDM2 properties. Compound <b>20i</b> (R&#xa0;= 4-MeOC<sub>6</sub>H<sub>4</sub>) is the most effective topo-I and topo-IIα inhibitor with potency close to that of the standard references (Dxd, and etoposide). Some of the synthesized agents showed selectivity for topo-IIα over topo-I. Molecular docking results (PDB: 4OAS) are consistent with the observed properties against MDM2. Based on the biological and biochemical findings, some of the synthesized compounds could serve as promising multi-targeted inhibitors.</p>

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Antineoplastic 4-piperidone-1-phosphonothioates with potential multi-targeted inhibitory properties

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月18日

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  • Mohamed S. Bekheit,
  • Siva S. Panda,
  • Benson M Kariuki,
  • Walid Fayad,
  • Ahmed A. F. Soliman,
  • Hanaa Farag,
  • Adel S. Girgis

摘要

A set of 3,5-bis(ylidene)-4-piperidone-1-phosphonothioates 20a‒l was synthesized in high yields through dehydrochlorination reaction of 3,5-bis(ylidene)-4-piperidones 18a‒l and diethyl chlorothiophosphate 19 in DMF containing quantitative amounts of TEA at 0 °C. Most of the synthesized agents exhibit effective antiproliferation properties against a variety of cancer cell lines (MCF7/breast, HCT116/colon, and A431/skin), outperforming the efficacy of the clinically approved drugs. Compound 20c (R = 3-ClC6H4) is the most effective analog discovered with a sub-micromolar activity against MCF7 (IC50 = 0.650, 3.15 and 3.97 µM, for 20c, 5-fluorouracil, and sunitinib, respectively) as well as remarkable efficacy against HCT116, and A431 (IC50 = 1.445 and 2.920 µM respectively for 20c, compared to 20.43 and 23.44 µM respectively for 5-fluorouracil). The synthesized analogs demonstrating considerable anti-MCF7 properties were evaluated for their biochemical properties against MDM2, p53, and topoisomerase I/II. Compound 20k [R = 3,4,5-(MeO)3C6H2] is the most effective anti-MDM2 agent with a potency higher than the standard reference (% inhibition of 65.3, for 20k, and 42.2 for doxorubicin; i.e. 1.55-fold). Biochemical activation of p53 by the synthesized analogs is consistent with the anti-MDM2 properties. Compound 20i (R = 4-MeOC6H4) is the most effective topo-I and topo-IIα inhibitor with potency close to that of the standard references (Dxd, and etoposide). Some of the synthesized agents showed selectivity for topo-IIα over topo-I. Molecular docking results (PDB: 4OAS) are consistent with the observed properties against MDM2. Based on the biological and biochemical findings, some of the synthesized compounds could serve as promising multi-targeted inhibitors.