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<p>Spiroindolin-2-ones with phosphonate function 17a‒t (20 analogs, 96‒72% yield) were generated by microwave synthetic methodology using azomethine cycloaddition of the appropriate 3,5-bis(ylidene)-4-piperidone-1-phosphonate 14a‒g. Single crystal X-ray analysis of 17d confirmed the structure. Promising 2D-monolayer antiproliferation properties (MTT assay) were observed for some of the synthesized agents with no harm to normal (RPE1) cell line. Compound 17h (R = 4-ClC<sub>6</sub>H<sub>4</sub>, R′ = H; IC<sub>50</sub> = 3.08&#xa0;μM; 6.6- and 3.1-fold the standard drugs, 5-fluorouracil and sunitinib, respectively) is the most distinguished agent against colon/HCT116 cell line. Compound 17f (R = 4-FC<sub>6</sub>H<sub>4</sub>, R′ = Cl; IC<sub>50</sub> = 5.252&#xa0;μM; 3.2-fold the activity of sunitinib, the clinically approved standard drug) also has significant activity against pancreatic/PaCa2 cell line. 3D-multicellular spheroid (HCT116) testing was also performed. Notable VEGFR-2 inhibitory properties were evident for some of the synthesized analogs. Considerable activity against COX-1/-2 and TNF-α, relative to the established NSAIDs ibuprofen and indomethacin, was also detected. CAM testing evidenced the anti-VEGFR-2 observations and anti-angiogenic properties. Internal and external validated QSAR models explored the functions necessary for the antiproliferation potency. In conclusion, the designed spiroindolin-2-ones conjugated with phosphonate function can be useful for optimizing novel anti-cancer therapeutic agent(s) with anti-angiogenic (anti-VEGFR-2) mode of action after considering more needed advanced pharmacological studies.</p>

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Antiproliferation, 3D-multicellular spheroid and VEGFR-2 inhibitory properties of spiroindolin-2-ones with phosphonate function

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月7日

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  • Sara M. Hassan,
  • Alyaa Farid,
  • Mohamed S. Bekheit,
  • Siva S. Panda,
  • Benson M. Kariuki,
  • Anwar Abdelnaser,
  • Soad Nasr,
  • Walid Fayad,
  • May A. El-Manawaty,
  • Ahmed A. F. Soliman,
  • Adel S. Girgis

摘要

Spiroindolin-2-ones with phosphonate function 17a‒t (20 analogs, 96‒72% yield) were generated by microwave synthetic methodology using azomethine cycloaddition of the appropriate 3,5-bis(ylidene)-4-piperidone-1-phosphonate 14a‒g. Single crystal X-ray analysis of 17d confirmed the structure. Promising 2D-monolayer antiproliferation properties (MTT assay) were observed for some of the synthesized agents with no harm to normal (RPE1) cell line. Compound 17h (R = 4-ClC6H4, R′ = H; IC50 = 3.08 μM; 6.6- and 3.1-fold the standard drugs, 5-fluorouracil and sunitinib, respectively) is the most distinguished agent against colon/HCT116 cell line. Compound 17f (R = 4-FC6H4, R′ = Cl; IC50 = 5.252 μM; 3.2-fold the activity of sunitinib, the clinically approved standard drug) also has significant activity against pancreatic/PaCa2 cell line. 3D-multicellular spheroid (HCT116) testing was also performed. Notable VEGFR-2 inhibitory properties were evident for some of the synthesized analogs. Considerable activity against COX-1/-2 and TNF-α, relative to the established NSAIDs ibuprofen and indomethacin, was also detected. CAM testing evidenced the anti-VEGFR-2 observations and anti-angiogenic properties. Internal and external validated QSAR models explored the functions necessary for the antiproliferation potency. In conclusion, the designed spiroindolin-2-ones conjugated with phosphonate function can be useful for optimizing novel anti-cancer therapeutic agent(s) with anti-angiogenic (anti-VEGFR-2) mode of action after considering more needed advanced pharmacological studies.