5‐(4‐Methoxybenzylidene)thiazolidine‐2,4‐dione‐derived VEGFR‐2 inhibitors: Design, synthesis, molecular docking, and anticancer evaluations

Abstract

A novel series of 5‐(4‐methoxybenzylidene)thiazolidine‐2,4‐dione derivatives, 5a–g and 7a–f, was designed, synthesized, and evaluated for their anticancer activity against HepG2, HCT116, and MCF‐7 cells. HepG2 and HCT116 were the most sensitive cell lines to the influence of the new derivatives. In particular, compounds 7f, 7e, 7d, and 7c were found to be the most potent derivatives of all the tested compounds against the HepG2, HCT116, and MCF‐7 cancer cell lines. Compound 7f (IC50 = 6.19 ± 0.5, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively) exhibited a higher activity than sorafenib (IC50 = 9.18 ± 0.6, 8.37 ± 0.7, and 5.10 ± 0.4 µM, respectively) against HepG2 and MCF‐7, cells but a lower activity against HCT116 cancer cells, respectively. Also, this compound displayed a higher activity than doxorubicin (IC50 = 7.94 ± 0.6, 8.07 ± 0.8, and 6.75 ± 0.4 µM, respectively) against HepG2 and MCF‐7 cells, but nearly the same activity against HCT116 cells, respectively. All derivatives, 5a–g and 7a–f, were evaluated for their inhibitory activities against vascular endothelial growth factor receptor‐2 (VEGFR‐2). Among them, compound 7f was found to be the most potent derivative that inhibited VEGFR‐2 at an IC50 value of 0.12 ± 0.02 µM, which is nearly the same as that of sorafenib (IC50 = 0.10 ± 0.02 µM). Compounds 7e, 7d, 7c, and 7b exhibited the highest activity, with IC50 values of 0.13 ± 0.02, 0.14 ± 0.02, 0.14 ± 0.02, and 0.18 ± 0.03 µM, respectively, which are more than the half of that of sorafenib. Furthermore, molecular docking was performed to investigate their binding mode and affinities toward the VEGFR‐2 receptor. The data obtained from the docking studies highly correlated with those obtained from the biological screening.

N‐Substituted‐4‐phenylphthalazin‐1‐amine‐derived VEGFR‐2 inhibitors: Design, synthesis, molecular docking, and anticancer evaluation studies

“…N ‐Substituted‐4‐phenylphthalazin‐1‐amine derivatives have the essential pharmacophoric features of VEGFR‐2 inhibitors [ 22,39‐44 ] (Figure 1), which include the following: First, there exists a six‐membered heteroaromatic ring, phthalazine, as a central aryl moiety, substituted with phenyl ring, as a hydrophobic portion, forming the 4‐phenylphthalazine scaffold. Second, the target phenyl group at position‐4 is used to replace pyridine and N ‐methylpicolinamide moieties of vatalanib and sorafenib (Figures 2 and 3), respectively.…”

“…In continuation of our efforts to obtain new anticancer agents, [ 37‐43 ] the goal of the present work was the synthesis of new agents with the same essential pharmacophoric features of the reported and clinically used VEGFR‐2 inhibitors (e.g., vatalanib and sorafenib). The main core of our molecular design rationale comprised bioisosteric modification strategies of VEGFR‐2 inhibitors at the four different pharmacophoric positions (Figure 1).…”

Design, synthesis, molecular docking, anticancer evaluations, and in silico pharmacokinetic studies of novel 5‐[(4‐chloro/2,4‐dichloro)benzylidene]thiazolidine‐2,4‐dione derivatives as VEGFR‐2 inhibitors

“…[ 21,22 ] Sorafenib (Nexavar®; IV ; (Figure 1) also is a potent VEGFR‐2 inhibitor and has been approved as an anti‐angiogenic drug. [ 23–25 ] Our reported compounds V [ 19 ] and VI [ 20 ] encourage us to synthesize new derivatives with the hydrophobic electron‐withdrawing mono‐, chloro‐, and/or dichlorobenzylidene instead of unsubstituted ( V ) or the hydrophobic electron‐donating methoxybenzylidenes ( VI ), respectively, to study the effect of these modifications on the activity.…”

“…A study reported by Shah et al, [12] showed that TZD derivative ciglitazone (I) ( Figure 1) significantly decreased the VEGF production in human granulose cells in an in vitro model. Extensive studies were reported in the synthesis of several 5-benzylidenethiazolidine-2,4-dione derivatives as potent anticancer agents [13][14][15][16][17][18][19][20] and potent VEGFR-2 inhibitors, for example, compound II. [2,12] Owing to the importance of VEGFR-2 in angiogenesis, this receptor is the most vital target in anti-angiogenic therapy against cancer.…”

Structure–activity relationship studies of indolin‐2‐one derivatives as vascular endothelial growth factor receptor inhibitors and anticancer agents

“…[19] Recently, different small molecules have been designed as VEGFR inhibitors and anticancer agents. [20][21][22][23][24][25][26][27][28] The indolin-2-one analogs have been identified as effective angiogenesis inhibitors and multitargeted tyrosine kinases inhibitors. Sunitinib (SU11248) is the first small molecule possessing the indolin-2-one template against a variety of kinases such as VEGF receptor (VEGFR) types 1 (FLT1), 2 (KDR), and 3 (FLT4); the stem cell factor receptor (c-Kit); platelet-derived growth factor receptors A and B (PDGFRA and PDGFRB); colony-stimulating factor 1 receptor (CSF-1R); FMS-like tyrosine kinase 3 (FLT3); and glial cell line-derived neurotrophic factor receptor (RET), which received FDA approval and was marketed for the treatment of gastrointestinal stromal tumor (GIST) and renal cell carcinoma (RCC) in January 2006, and for pancreatic neuroendocrine tumors in May 2011.…”