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

Abstract

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.

Novel 2-Aminobenzothiazole Derivatives: Docking, Synthesis, and Biological Evaluation as Anticancer Agents

“…The study found that the IC 50 values for doxorubicin and gedatolisib were 16.61 and 16.46 μM against A549 cancer cell lines (Table ), respectively, while the reported IC 50 for gedatolisib was 9.05 μM. , The reported IC 50 for doxorubicin against A549 was 0.071 μM. − The most active synthesized compound (OMS14) was tested against cancer enzymes other than PI3Kγ, and the result is shown in Table .…”

Synthesis of novel coumarin-triazole hybrids and first evaluation of the 4-phenyl substituted hybrid loaded PLGA nanoparticles delivery system to the anticancer activity

“…, 2.57 (t, 2H, J = 6.0 Hz, CH 2 ), 2.76 (t, 2H, J = 6.0 Hz, CH 2 ), 3.39 (t, 2H, J = 6.5 Hz, CH 2 N 3 ), 4.05 (t, 2H, J = 6.0 Hz, OCH 2 ), 6.79 (bd, 1H, J = 2.5 Hz, ArH), 6.84 (dd, 1H, J = 9.0 Hz, 2.5 Hz, ArH), 7.47 (d, 1H, J = 9.0 Hz, ArH). 13 General procedure for the synthesis of coumarintriazole hydrids (16)(17)(18)(19)(20)(21) Azidoalkyloxy compound (0.138 mmol), phenylacetylene (0.16 mmol) and CuI (0.41 mmol) were mixed in tetrahydrofurane (5 ml) for 48 h at room temperature. Then, the mixture was filtered over celite.…”

“…The MTT assay described before was performed by inoculating cultured MCF-7 and HeLa cells (the number of cells was 10 4 cells per well) [48]. The six compounds (16)(17)(18)(19)(20)(21) were added to wells in a concentrations of 1 mg ml −1 in four replicate (n = 4) after 24 h of seeding in DMEM-F12 medium including 10% FBS. The cells were incubated for 24 h and 48 h periods of time.…”

“…Coumarin and 1,2,3-trizole rings are important pharmacophore systems. Their combination in a hybrid molecule promise important biological activities [16][17][18][19][20]. Therefore, recently there has been a growing interest among researchers in the synthesis an evaluation of novel coumarin-triazole hybrid molecules.…”