Design, synthesis, and screening of ortho-amino thiophene carboxamide derivatives on hepatocellular carcinomaas VEGFR-2Inhibitors

Abstract

In this work, design, synthesis, and screening of thiophene carboxamides 4–13 and 16–23 as dual vascular endothelial growth factor receptors (VEGFRs) and mitotic inhibitors was reported. All compounds were screened against two gastrointestinal solid cancer cells, HepG-2 and HCT-116 cell lines. The most active cytotoxic derivatives 5 and 21 displayed 2.3- and 1.7-fold higher cytotoxicity than Sorafenib against HepG-2 cells. Cell cycle and apoptosis analyses for compounds 5 and 21 showed cells accumulation in the sub-G1 phase, and cell cycle arrest at G2/M phase. The apoptotic inducing activities of compounds 5 and 21were correlated to the elevation of p53, increase in Bax/Bcl-2 ratio, and increase in caspase-3/7.Compounds 5 and 21 showed potent inhibition againstVEGFR-2 (IC50 = 0.59 and 1.29 μM) and β-tubulin polymerization (73% and 86% inhibition at their IC50 values).Molecular docking was performed with VEGFR-2 and tubulin binding sites to explain the displayed inhibitory activities.

Design, Synthesis, Molecular Modeling and Antitumor Evaluation of Novel Indolyl-Pyrimidine Derivatives with EGFR Inhibitory Activity

“…This was followed-up by hydrazinolysis of the ester group of intermediate 1 using hydrazine hydrate in ethanol to form compound 2 . Then, hydrazone derivatives 3a – h were prepared from compound 2 via heating with the appropriate aromatic aldehydes either in absolute ethanol only or with acetic acid as a catalyst [ 52 ] ( Scheme 1 ).…”

Design, synthesis, and cytotoxicity screening of new synthesized imidazolidine‐2‐thiones as VEGFR‐2 enzyme inhibitors

“…Meanwhile, the tail is formed from a linker attached to hydrophobic aryl groups to increase binding affinity for enzyme sites. [3,15] Furthermore, literature reports indicate that thiazole derivative 4 ( Figure 1) exhibited promising PK inhibition activities as SOR. [16] From the above-mentioned findings, herein, we reported the fused sodium acetate under reflux, following the reported procedure.…”

“…The targeted anticancer molecules interfere with specific cellular targets such as angiogenesis, tubulin, and DNA present in cancer cells and normal cells. [1][2][3][4] Angiogenesis, the formation of new blood vessels from the existing ones, is a fundamental process in the pathogenesis of various disorders including cancer. [5,6] Tumor angiogenesis is a prerequisite for tumor metastasis, and it is a crucial factor in cancer growth and progression.…”

“…Meanwhile, the tail is formed from a linker attached to hydrophobic aryl groups to increase binding affinity for enzyme sites. [ 3,15 ] Furthermore, literature reports indicate that thiazole derivative 4 (Figure 1) exhibited promising PK inhibition activities as SOR. [ 16 ]…”

Novel VEGFR‐2 inhibitors with an N‐acylhydrazone scaffold

“…[47,48] In these derivatives, the intramolecular hydrogen bond is stable under biological conditions and promotes a conformational constraint that could mimic the bicyclic system of 5 during ligand-target recognition. [48][49][50] Motesanib (7; AMG 706; Figure 1) is also a VEGFR-2 inhibitor [51,52] (IC 50 = 3 nM) [53] with similar structural characteristics. [54] Compound OSI-930 (8; Figure 1), bearing a thiophene moiety, is a VEGFR-2 inhibitor prototype (IC 50 = 9 nM), [55] which is also able to form a similar intramolecular hydrogen bond.…”