Triple-negative breast cancer (TNBC) is one of the most aggressive and metastatic forms of breast cancer, for which there are currently no satisfactory therapeutic agents. Here, we reported for the first time that boholamide A, a naturally occurring macrocyclic depsipeptide, exhibited hypoxia-selective anti-TNBC activity against in MDA-MB-231 cells. However, its structure-activity relationships and target had not yet been elucidated. A series of boholamide A analogues were chemically synthesized and evaluated for anti-TNBC potency. The most promising compound 1j was prepared in 13 linear steps with an overall yield of 7.92%, and exhibited high potency against MDA-MB-231 cells with an IC₅₀ value of 0.15 μmol/L under hypoxic condition. Moreover, 1j significantly inhibited proliferation and migration, and induced apoptosis in MDA-MB-231 cells. Compound 16, a prodrug of 1j, significantly inhibited the tumor volume and tumor weight in xenografts. Furthermore, we identified that 1j covalently targeted eukaryotic translation elongation factor 1alpha 1 (eEF1A1) which might underlie the anticancer activity and hypoxia selectivity of boholamide A analogues. These results suggested that boholamide A analogues represented a promising scaffold for discovering hypoxia-selective anti-TNBC agents, and compound 16 deserved further investigation as a candidate for TNBC treatment.

Boholamide A analogue  /  Hypoxia selectivity  /  eEF1A1  /  Triple-negative breast cancer