Synthesis, DFT analysis and in-vitro anti-cancer study of novel fused bicyclic pyranone isoxazoline derivatives of Goniodiol-diacetate-a natural product derivative

Abstract

Natural products, natural product-inspired molecules and natural product derivatives have contributed around 79 percent to the new chemotherapies against the most complex, deadly disease, cancer. In this study, a series of novel isoxazoline derivatives of Goniodiol diacetate (fused bicyclic pyranone isoxazoline derivatives)- a natural product derivative, were synthesized with quantitative yield as a single regioisomer by 1,3 - dipolar cycloaddition reaction with different aldoximes. The regiospecific product formed was confirmed by NOESY study and single-crystal X-ray diffraction. The regiospecificity of the product formation was further explained by coefficients of selected atomic orbitals in frontier molecular orbitals and natural population analysis (NPA in eV) of dipolarophile and dipole by density functional theory studies. All the derivatives have demonstrated anti-cancer activity selectively in human breast cancer (MDA-MB-231), ovarian cancer (SKOV3), prostate cancer (PC-3) and colon cancer (HCT-15) cell lines with EC sub(50) less than 10 mu M. Additionally, Annexin V/PI assay and cell cycle analysis on selected potent compound 3 f exhibited tuned apoptotic response & necrosis compared to standard Vincristine and showed cell growth arrest at the S phase.