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

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.