Potential Anticancer Agents Based on Monoterpenic Skeleton With Mono and Bis-Isoxazoline Derivatives: Diastereoselective Synthesis, Experimental Study, Evaluation of Biological Activity, and Molecular Docking

Abstract

A facile synthesis of fused isoxazolines has been carried out using a 1,3-dipolar cycloaddition reaction of arylonitrile oxides on (R)-Carvone under different stoichiometry conditions. The newly synthesized compounds were fully characterized via spectroscopic analysis and then evaluated for their in vitro antiproliferative properties against four cancer cell lines, namely HT1080, MCF-7, MDA-MB-231, and A-549. All the mono-isoxazolines showed low cytotoxicity (> 100 μM) and the large majority of bis-isoxazolines revealed moderate antiproliferative activity. The derivative 11b was the most potent one against HT-1080 and MDA-MB-231 with respective IC₅₀ values of 14.85 and 15.37 μM. A comprehensive study also showed that bis-isoxazoline 11b induced apoptosis involving a mitochondria-mediated signaling pathway and cell cycle arrest at the G0/G1 phase for HT-1080 and G2/M for MDA-MB-231. Finally, compound 11b showed a high binding affinity in the molecular docking study at the binding pockets of the Caspase-3 and Bcl-2 proteins, consistent with the results of biological experiments. Furthermore, this anticancer activity may be triggered by binding to active sites of caspase-3 and Bcl-2.