Inhibition of Vascular Smooth Muscle and Cancer Cell Proliferation by New VEGFR Inhibitors and Their Immunomodulator Effect: Design, Synthesis, and Biological Evaluation

Abstract

Abnormal vascular smooth muscle cell (VSMC) proliferation has an important role in the pathogenesis of both atherosclerosis restenosis and hypertension. Vascular endothelial growth factor (VEGF) has been shown to stimulate VSMC proliferation. In addition, angiogenesis is one of the hallmarks of cancerous growth. VEGF is the key modulator for the initial stages of angiogenesis that acts through the endothelial-specific receptor tyrosine kinases (VEGFRs). VEGFR-2 blockage is a good approach for suppression of angiogenesis. In order to discover novel VEGFR-2 TK inhibitors, we have designed and synthesized three new series of pyridine-containing compounds. The new compounds were all screened against a panel of three cell lines (HepG-2, HCT-116, and MCF-7). Promising results encouraged us to additionally evaluate the most active members for their in vitro VEGFR-2 inhibitory effect. Compound 7a, which is the most potent candidate, revealed a significant increase in caspase-3 level by 7.80-fold when compared to the control. In addition, Bax and Bcl-2 concentration levels showed an increase in the proapoptotic protein Bax (261.4 Pg/ml) and a decrease of the antiapoptotic protein Bcl-2 (1.25 Pg/ml) compared to the untreated cells. Furthermore, compound 7a arrested the cell cycle in the G2/M phase with induction of apoptosis. The immunomodulatory effect of compound 7a, the most active member, showed a reduction in TNF-α by 87%. Also, compound 7a caused a potent inhibitory effect on smooth muscle proliferation. Docking studies were also performed to get better insights into the possible binding mode of the target compounds with VEGFR-2 active sites.

Discovery of new nicotinamides as apoptotic VEGFR-2 inhibitors: virtual screening, synthesis, anti-proliferative, immunomodulatory, ADMET, toxicity, and molecular dynamic simulation studies

“…Comparing the in vitro anti-proliferative activity of compound D-1 (the most active member) with the previously published lead compounds 21 , indicated that compound D-1 showed a higher cytotoxic effect against HCT-116 and HepG-2. The cytotoxicity of our published compounds were ranging from 1.94 to 31.70 µM against HCT-116 and from 2.23 to 31.45 µM against HepG-2.…”

“…The pyridine-based derivatives A-1, B-1, C-6, and D-1 were synthesised according to the reactions illustrated in Scheme 1 . Nicotinic acid 2 underwent a chlorination reaction with thionyl chloride to give nicotinoyl chloride 3 21 . Nicotinoyl chloride 3 was then reacted with 4-aminoacetophenone to afford N -(4-acetylphenyl)nicotinamide 4 .…”

“…All the reagents, chemicals, and apparatus were described in Supplementary data . Compounds 3 and 4 were prepared according to the reported procedures 21 .…”

“…In this regard, we have introduced several small molecules that were efficiently proved to possess strong VEGFR-2 inhibitory activities that were, in some cases, higher than that of the reference drugs. One of the most promising skeletons in our research project was the pyridine scaffold 21 . Pyridine was the backbone of several well-known VEGFR-2 inhibitors 22–24 .…”

Design, Molecular Docking, Synthesis, Anticancer and Anti-Hyperglycemic Assessments of Thiazolidine-2,4-diones Bearing Sulfonylthiourea Moieties as Potent VEGFR-2 Inhibitors and PPARγ Agonists

“…In continuance of our earlier works in the scope of the design and syntheses of novel anticancer medicines [36][37][38][39][40][41][42][43][44], particularly VEGFR-2 inhibitors [45][46][47][48][49][50][51][52][53][54], thiazolidine-2,4-diones bearing sulfonylthiourea moieties were synthesized to obtain the four keys of VEGFR-2 inhibitors pharmacophoric features (Figure 3) [55][56][57]. The focus of the current study was to utilize the lead modification approach for sorafenib, a potent VEGFR-2 inhibitor, to obtain novel potent inhibitors.…”