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Induction of premature senescence represents a novel functional strategy to curb the uncontrolled proliferation of malignant cancer cells. This study unveils the regiospecific synthesis of novel isoxazoline derivatives condensed to ring A of medicinal plant product Withaferin-A. Intriguingly, the  cis  fused products with β-oriented hydrogen exhibited excellent cytotoxic activities against proliferating human breast cancer MCF7 and colorectal cancer HCT-116 cells. The most potent derivative  W-2b  triggered premature senescence along with increase in senescence-associated β-galactosidase activity, G2/M cell cycle arrest, and induction of senescence-specific marker p21 Waf1/Cip1  at its sub-toxic concentration.  W-2b  conferred a robust increase in phosphorylation of mammalian checkpoint kinase-2 (Chk2) in cancer cells in a dose-dependent manner. Silencing of endogenous Chk2 by siRNA divulged that the amplification of p21 expression and senescence by  W-2b  was Chk2-dependent. Chk2 activation (either by ectopic overexpression or through treatment with  W-2b ) suppressed NM23-H1 signaling axis involved in cancer cell proliferation. Finally,  W-2b  showed excellent  in vivo  efficacy with 83.8% inhibition of tumor growth at a dose of 25 mg/kg, b.w. in mouse mammary carcinoma model. Our study claims that  W-2b  could be a potential candidate to limit aberrant cellular proliferation rendering promising improvement in the treatment regime in cancer patients.

Regiospecific Synthesis of Ring A Fused Withaferin A Isoxazoline Analogues: Induction of Premature Senescence by W-2b in Proliferating Cancer Cells