Synthesis, molecular docking, and apoptogenic efficacy of novel N-heterocycle analogs to target B-cell lymphoma 2/X-linked inhibitors of apoptosis proteins to regress melanoma

Abstract

The novel series of piperidine conjugated benzophenone analogs with amide link 11a–l were synthesized in a multistep process. The structures of these compounds were confirmed by IR, 1H, 13C, NMR, and mass spectra and also by elemental analyses. The newly synthesized molecules were screened for selectivity against cancers of different origin through cell based assay system using B16F10, A375, A549, HepG2, ACHN, and MCF7 cells. The results postulated that compound 11f with two bromo groups at the para position in rings A and E and two methyl groups at ortho position in rings B and D evokes target specific action against melanoma highlighting the importance of substituted groups. Down the line studies further inferred compound 11f evokes the apoptotic cellular event leading to cell death. Investigation of eventual mechanism revealed that compound 11f turned out to be a dual inhibitor of B-cell lymphoma-2 and X-linked inhibitors of apoptosis causing the up regulation of Bax and Bad. Further, the antiproliferative effects were mimicked in murine melanoma with similar mechanisms. Molecular docking experiments further confirmed that compound 11f possessed a superior affinity for of B-cell lymphoma-2 and X-linked inhibitors of apoptosis through strong hydrogen bonds. The study implies the identification of compound 11f with selective target against melanoma by inducing apoptogenic effect, which could be the future hope for the treatment of skin cancer.