Targeting cell cycle and apoptotic pathways with newly synthesized diselenide-linked imidazolone analogues with strong CDK6-targeting potential

Abstract

A novel panel of diselenide-linked imidazolone derivatives was synthesized and biologically profiled, revealing a promising new chemotype with broad-spectrum anticancer activity. Among the series, compounds 6b, 6d, and 6g demonstrated exceptional growth-inhibitory (GI) potency, achieving GI% values of 80.32%, 79.24%, and 86.40%, respectively—substantially outperforming doxorubicin (61.49%). Notably, 6g emerged as the lead candidate, exhibiting robust cytotoxicity across diverse cancer models with IC₅₀ values of 6.49 µM (PC3), 6.58 µM (MCF7), 5.38 µM (A549), and 7.25 µM (HCT₁₁₆). Mechanistic studies in A549 cells indicated that 6g simultaneously modulates multiple oncogenic pathways: it markedly downregulated CDK2, CDK4, and CDK6 (1.57–4.12 fold), while upregulating caspase-3, caspase-8, and caspase-9 (1.60–1.64 fold), collectively supporting its dual action on cell-cycle blockade and apoptotic activation. Furthermore, a 1.68-fold reduction in VEGFR-2 expression underscores its additional anti-angiogenic potential. Flow cytometry corroborated these findings, revealing a dramatic S-phase arrest, with the S-phase population rising from 4.61% to 42.09% upon treatment. Several other analogues, including 6d, 6e, 6i, and 6j, also displayed potent cytotoxicity (IC₅₀ < 10 µM), highlighting the broader therapeutic relevance of this scaffold. Collectively, these data position 6g as a compelling multi-target anticancer lead that integrates apoptosis induction, cell-cycle regulation, and angiogenesis suppression—supporting its potential for development as a next-generation broad-spectrum anticancer agent.