Design and development of novel 1,2,3-triazole chalcone derivatives as potential anti-osteosarcoma agents via inhibition of PI3K/Akt/mTOR signalling pathway

by Selleckchem | Mar 27 2023

Osteosarcoma (OS) is an uncommon tumour that mainly affects bone in children and adolescents. The current treatment options of OS are of limited significance due to their immense side effects. In the present manuscript, we have developed a novel series of 1,2,3-triazole chalcone derivatives as potential agents against OS. The compounds were synthesized and evaluated for their PI3K and mTOR inhibitory activity using luminescent kinase assay, and Lance ultra assay, resp. The entire set of compounds showed significant to moderate inhibition of both kinases in the nanomolar range. The three most active compounds: 4e (N-(4-(3-(1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)acryloyl)phenyl)-4-nitrobenzamide), 4f (N-(4-(3-(1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)acryloyl)phenyl)-4-chlorobenzamide) and 4g (4-bromo-N-(4-(3-(1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)acryloyl)phenyl)benzamide), were evaluated for anticancer activity against human OS cancer cell line (MG-63), liver cancer cell line (HepG2), lung cancer cell line (A549) and cervical cancer (HeLa), using MTT assay. Among the tested series, compound 4e showed a better inhibitory profile than gedatolisib against PI3K and was approximately comparable to that of gedatolisib against mTOR. The most significant inhibitory activity was observed for compound 4e against all cell lines (MG-63, HepG2, A549 and HeLa), still somewhat lower to comparable to that of gedatolisib, but with the highest potency against MG-63 cells. Compound 4e was further tested for anti-cancer activity against other OS cells and showed to be equipo-tent to gedatolisib against U2OS and Saos-2 cells. Moreover, it was also found non-toxic to normal cells (BEAS-2B and MCF 10A). The effect of compound 4e was further determined on apoptosis of Saos-2 cells by Annexin-PI assay, where it significantly amplified the percentage of apoptotic cells. Novel 1,2,3-triazole chalcone derivatives are potential agents against OS.

Comments：

The present manuscript reports the development of a series of novel 1,2,3-triazole chalcone derivatives as potential agents against osteosarcoma (OS), a rare bone tumor that primarily affects children and adolescents. The compounds were synthesized and evaluated for their inhibitory activity against PI3K and mTOR, two kinases that are frequently overexpressed in cancer cells.

The results of the study showed that all of the synthesized compounds demonstrated significant to moderate inhibition of both kinases in the nanomolar range. The three most active compounds, 4e, 4f, and 4g, were further evaluated for their anticancer activity against several cancer cell lines, including OS cell line MG-63, liver cancer cell line HepG2, lung cancer cell line A549, and cervical cancer cell line HeLa, using MTT assay. Among these compounds, 4e showed the best inhibitory profile against all cell lines, with the highest potency against MG-63 cells.

Compound 4e was further tested for its anti-cancer activity against other OS cells, and the results showed that it was equipotent to gedatolisib, a known PI3K/mTOR inhibitor, against U2OS and Saos-2 cells. Moreover, it was found to be non-toxic to normal cells BEAS-2B and MCF 10A. The effect of compound 4e was also determined on apoptosis of Saos-2 cells, and the results indicated that it significantly increased the percentage of apoptotic cells.

Overall, the findings suggest that the novel 1,2,3-triazole chalcone derivatives developed in this study have the potential to be effective agents against OS, with compound 4e showing the most promising anti-cancer activity. Further studies are warranted to investigate the efficacy of these compounds in preclinical and clinical settings.