Novel N-Arylmethyl-aniline/chalcone hybrids as potential VEGFR inhibitors: synthesis, biological evaluations, and molecular dynamic simulations.

Significant advancements have been made in the domain of targeted anticancer therapy for the management of malignancies in recent times. VEGFR-2 is characterised by its pivotal involvement in angiogenesis and subsequent mechanisms that promote tumour cells survival. Herein, novel N-arylmethyl-aniline/chalcone hybrids 5a-5n were designed and synthesised as potential anticancer and VEGFR-2 inhibitors. The anticancer activity was evaluated at the NCI-USA, resulting in the identification of 10 remarkably potent molecules 5a-5j that were further subjected to the five-dose assays. Thereafter, they were explored for their VEGFR-2 inhibitory activity where 5e and 5h emerged as the most potent inhibitors. 5e and 5h induced apoptosis with cell cycle arrest at the SubG0-G1 phase within HCT-116 cells. Moreover, their impact on some key apoptotic genes was assessed, suggesting caspase-dependent apoptosis. Furthermore, molecular docking and molecular dynamics simulations were conducted to explore the binding modes and stability of the protein-ligand complexes.

New phenothiazine conjugates as apoptosis inducing agents: Design, synthesis, In-vitro anti-cancer screening and 131I-radiolabeling for in-vivo evaluation.

Phenothiazines (PTZs) are a group of compounds characterized by the presence of the 10H-dibenzo-[b,e]-1,4-thiazine system. PTZs used in clinics as antipsychotic drugs with other diverse biological activities. The current aim of the study is to investigate and understand the effect of potent PTZs compounds using a group of In-vitro and In-vivo assays. A total of seventeen novel phenothiazine derivatives have been designed, synthesized, and evaluated primarily in-vitro for their ability to inhibit proliferation activity against NCI-60 cancer cell lines, including several multi-drug resistant (MDR) tumor cell lines. Almost all compounds were active and displayed promising cellular activities with GI50 values in the sub-micromolar range. Four of the most promising derivatives (4b, 4h, 4g and 6e) have been further tested against two selected sensitive cancer cell lines (colon cancer; HCT-116 and breast cancer; MDA-MB231). The apoptosis assay showed that all the selected compounds were able to induce early apoptosis and compound 6e was able to induce additional cellular necrosis. Cell cycle assay showed all selected compounds were able to induce cell cycle arrest at sub-molecular phase of G0-G1 with compound 6e induced cell cycle arrest at G2M in HCT-116 cells. Accordingly, the apoptotic effect of the selected compounds was extensively investigated on genetic level and Casp-3, Casp-9 and Bax gene were up-regulated with down-regulation of Bcl-2 gene suggesting the activation of both intrinsic and extrinsic pathways. In-vivo evaluation of the antitumor activity of compound 4b in solid tumor bearing mice showed promising therapeutic effect with manifestation of dose and time dependent toxic effects at higher doses. For better evaluation of the degree of localization of 4b, its 131I-congener (131I-4b) was injected intravenously in Ehrlich solid tumor bearing mice that showed good localization at tumor site with rapid distribution and clearance from the blood. In-silico study suggested NADPH oxidases (NOXs) as potential molecular target. The compounds introduced in the current study work provided a cutting-edge phenothiazine hybrid scaffold with promising anti-proliferation action that may suggest their anti-cancer activity.