Discovery of novel tris-1,2,3-triazole-based hybrids as VEGFR2 inhibitors with potent anti-proliferative and cytotoxicity through apoptosis induction.

The discovery of novel anti-cancer drugs motivated us to synthesize a new series of triple 1,2,3-triazole-based arm scaffolds featuring distinct un functionalized alkyl and/or aryl side chains with possible anti-cancer action using the click chemistry approach under both conventional and green microwave irradiation (MWI) methods. The Cu(I) catalyzed cycloaddition reaction of targeted tris-alkyne with un functionalized aliphatic and aromatic azides has been adopted as an efficient approach for synthesizing the desired click adducts. Microwave irradiation improved the synthetic processes, resulting in higher yields and faster reaction times. Spectroscopic techniques (FT-IR, H, C NMR andCHN analysis) were used for the elucidation of the resulting click structures. The newly synthesized tris-1,2,3-triazoles exhibited promising cytotoxicity, particularly compounds 26 and 28, with IC values of 22.18 µM and 20.3 µM against A549 and CaCo-2 cells, respectively. While they had IC values of 23.06 µM and 21.91 µM against T-47D and CaCo-2 cells, respectively. Both compounds exhibited promising anti-proliferative activity through the wound healing assay. Additionally, both compounds induced total apoptotic cell death by 68.3 % and 58.5 %, respectively, compared to untreated cells (7.7 %). Furthermore, they induced necrotic cell death by 1.4 % and 10.5 %, respectively, compared to 0.1 % in the untreated cells. For the molecular target, compounds 26 and 28 exhibited potent VEGFR2 inhibition with IC values of 35.5 nM and 27.8 nM, respectively, and this was highlighted through the molecular docking findings. Tris-1,2,3-triazoles (26 and 28) exhibited promising cytotoxicity and anti-proliferative against T-47D breast cancer cells through apoptosis and VEGFR2 inhibition using both enzyme kit and western blotting protein expression assays. Molecular docking study highlighted the binding affinity of tested compounds towards the VEGFR2 protein. Accordingly, tris-1,2,3-triazoles (26 and 28) can be further developed as more potent anti-cancer agents.