| Summary: | Background and purpose: Breast cancer remains a significant global health burden, especially in low-resource settings where standard therapies are limited. This study aimed to explore Mallotus glomerulatus, a lesser-known Thai medicinal plant, as a potential source of novel anti-breast cancer agents. Experimental approach: A phytochemical investigation of M. glomerulatus resulted in the isolation and structural characterization of a novel xanthone (Compound 1) and cleistanthin A (Compound 10) using UV, IR, NMR, and HRMS techniques. Cytotoxicity of the compounds was evaluated in vitro against MCF-7 (ER-positive) and MDA-MB-231 (triple-negative) breast cancer cell lines, along with HepG2 liver cells. Molecular docking studies were conducted to assess their interaction with vacuolar H+-ATPase (V-ATPase). Key results: Compound 1 demonstrated selective cytotoxicity toward MCF-7 cells, whereas cleistanthin A exhibited potent cytotoxicity against both breast cancer lines, with nanomolar IC50 values and a high selectivity index (>100) for MDA-MB-231 compared to HepG2 cells. Docking analysis revealed favourable binding of both compounds at the a–c subunit interface of V-ATPase, suggesting a mechanism involving proton pump inhibition and lysosomal dysfunction. Conclusion: The findings highlight M. glomerulatus, particularly cleistanthin A, as a promising source of safe and affordable anti-breast cancer compounds with potential therapeutic value. Further studies on the mechanism and in vivo efficacy are warranted.
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