A thiazole-based hydroxamic acid derivative induces mitochondrial apoptosis and S-phase arrest in MCF-7 cells via DNA minor groove binding.

Breast cancer remains a leading cause of cancer-related mortality in women globally. Approved chemotherapeutics, while effective, are associated with severe side effects, necessitating the development of safer, more targeted treatments. Our present study investigated the therapeutic potential of a thiazole-based hydroxamic acid derivative, 1, against MCF-7 breast cancer cells. 1 exhibited potent cytotoxicity with an IC of 21.18 ± 2.01 μM, comparable to the cytotoxicity of doxorubicin IC of 18.08 ± 1.20 μM, yet demonstrated excellent selectivity with no significant cytotoxicity towards normal MCF-10A epithelial cells (62.37 ± 1.01 μM). Swiss ADME analysis confirmed its favourable drug-likeness and non-PgP substrate status. Flow cytometric analysis confirmed that 1 demonstrated substantial apoptotic cell death, inducing 45 % apoptosis compared to 2.62 % in the control group, by 75.8 % mitochondrial membrane depolarization and S-phase cell cycle arrest (with cell accumulation reaching 30.1 % at 24 h). Spectroscopic and computational studies inferred the minor-groove binding ability of 1 towards CT-DNA. Immunoblotting confirmed the DNA damage response (upregulation of γH2AX and p-ATM expression) which activated the intrinsic apoptotic pathway (upregulation of p53 and Bax/Bcl-2 ratio from 1.1 in control to 4 following treatment and cleaved caspase-7). The induction of DNA damage was also visualized by increase in the comet tail moment (1 induced a tail moment of 54.75 ± 1.50 vs. 11.79 ± 2.23 for control). Subacute toxicity in BALB/c mice confirmed 1's safety, with no adverse liver, renal, biochemical or hematological effects up to 10 mg/kg. Collectively, the findings identify 1's potential as a chemotherapeutic lead agent for breast cancer.