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• Novel withangulatin A derivatives were synthesized and evaluated. • Compound 10 showed 70-fold higher anti-proliferative activity than withangulatin A. • Compound 10 induced cell cycle arrest in G2 phase. • Compound 10 caused MDA-MB-231 cells apoptosis through increasing intracellular ROS. • Compound 10 was a potential anticancer agent with high efficiency and low toxicity. Novel withangulatin A (WA) derivatives were synthesized and evaluated for antiproliferative activity against four human cancer cell lines (U2OS, MDA-MB-231, HepG2, and A549). Among these derivatives, 10 exhibited the most potent antiproliferative activity, with an IC 50 value of 74.0 nM against the human breast cancer cell line MDA-MB-231 and potency that was 70-fold that of WA (IC 50 = 5.22 µM). Moreover, 10 caused G2-phase cell cycle arrest in a concentration-dependent manner and induced the apoptosis of MDA-MB-231 cells by increasing intracellular reactive oxygen species (ROS). Compound 10 showed a high selectivity index (SI = 267.03) for breast cancer MDA-MB-231 cells. These results suggest that 10 is a promising anticancer agent. [ABSTRACT FROM AUTHOR]