Targeting VEGFR-2 with piperazine bridged indolin-2-one derivatives

As a key mediator of tumor angiogenesis, VEGFR-2 has emerged as a promising therapeutic target for combating Cancer. In the present study, a series of 6-substituted-3-(4-(4-(substitutedphenyl/benzyl)piperazin-1-yl)benzylidene) indolin-2-one derivatives (2-24) were synthesized in good yields and structurally confirmed by IR, NMR, and HRMS analyses. Several compounds exhibited strong VEGFR-2 inhibition, with activities comparable to or exceeding that of sorafenib, but lower than sunitinib. Cytotoxicity assays against MCF-7 breast Cancer cells revealed five derivatives (4, 7, 9, 10, and 12) more active than doxorubicin along with five additional compounds showing comparable potency. In contrast, the compounds displayed moderate cytotoxic activity against the MDA-MB-231 cell line and none showed significant toxicity toward MCF-10A normal breast epithelial cells. Mechanistic studies of compound 10 demonstrated G0/G1 phase arrest, Apoptosis induction, and increased ROS generation, suggesting its potential as a selective and effective lead for breast Cancer therapy.

Cytotoxic effect; Indolin-2-one; Molecular docking; Piperazine; VEGFR-2 inhibition.