Furan- and Furopyrimidine-Based Derivatives: Synthesis, VEGFR‑2Inhibition, and In Vitro Cytotoxicity

<p dir="ltr">New derivatives 4a−d, 6, 7a−d, 8a−c, 9, 11a, 11b,12a−f, 13a−c, and 14 were synthesized and evaluated for theirVEGFR-2 inhibition. Compounds 4c, 7b, and 7c showed remarkable enzyme inhibition (IC50 = 57.1, 42.5, and 52.5 nM, respectively) relative to sorafenib (IC50 = 41.1 nM) and were assessed for their cytotoxicity versus HepG2, MCF-7, A549, HT-29, and PC3 cancer cell lines in addition to WI-38. Compound 7bdisplayed nearly equipotent cytotoxicity against A549 and HT-29(IC50 = 6.66 and 8.51 μM) compared to sorafenib (IC50 = 6.60 and8.78 μM). Cell cycle analysis and apoptotic assay of 7b in the HT-29 cell line showed cellular growth arrest at the G2/M phase in addition to the induction of apoptosis. Western blot analysis of compound 7b revealed the deactivation of VEGFR-2. Moreover, a wound healing assay of 7b showed inhibition of wound closure. Additionally, molecular modeling studies of compounds 4c, 7b, and7c were carried out.