Evaluation of new 5-benzylidenethiazolidin-2,4-dione derivatives linked to nitric oxide donor oxime moiety as VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, anti-proliferative assessment and in silico studies.

AIM: Approaching VEGFR-2 blockers, two novel series of 5-benzylidenethiazolidine-2,4-dione 16c-f and 17a-f were synthesized.

METHODS: Screening against MCF-7 and HCT-116 cancer cell lines.

RESULTS: Derivatives 17c, 17d, 17e, and 17f employed cytotoxicity against MCF-7 (22.75% to 55.30%) (Doxorubicin = 87.6%). Compound 17d presented IC50 of 90.70 µM for MCF-7 (Doxorubicin = 32.36 µM). Concerning HCT-116 cell line, compounds 17d, 17e, and 17f haunted % inhibition (59.15% to 83.76%) (Doxorubicin = 96.8%). Besides, 17d, 17e, and 17f exhibited HCT-116 IC50 of 36.11, 54.50, and 67.22 µM, respectively (Doxorubicin = 21.27 µM). Also, compounds 17d, 17e, and 17f disclosed safety outlines alongside normal cell BJ IC50 (109.5 to 165 µM) (Doxorubicin = 38.51 µM). Compound 17earrested cell cycle at G2/M stage. Compounds 17a-f released NO potentiating anti-cancer activity. 17d, 17e, and 17f inhibit VEGFR-2 (IC50 of 50.0 nM, 23.0 nM, and 111.0 nM, respectively) and sunitinib (84.0 nM). Western blot results displayed compound 17e notable inhibition of the VEGFR-2/Akt/ERK axis. Docking studies revealed derivatives 17d-f docking score of -8.3 to -8.9 Kcal/Mol comparable to sunitinib and sorafenib.

CONCLUSION: The present work flags the approach for advanced expansion of powerful nitric oxide donor offshoots as VEGFR-2 inhibitors.