Total Synthesis of Lipopeptide Bacilotetrin C: Discovery of Potent Anticancer Congeners Promoting Autophagy

A convergent strategy for the first total synthesis of the lipopeptide bacilotetrin C has been developed. The key features of this synthesis include Crimmins acetate aldol, Steglich esterification, and macrolactamization. Twenty-nine variants of the natural product were prepared following a systematic structure–activity relationship study, where some of the designed analogues showed promising cytotoxic effects against multiple human carcinoma cell lines. The most potent analogue exhibited a ∼37-fold enhancement in cytotoxicity compared to bacilotetrin C in a triple-negative breast cancer (MDA-MB-231) cell line at submicromolar doses. The study further revealed that some of the analogues induced autophagy in cancer cells to the point of their demise at doses much lower than those of known autophagy-inducing peptides. The results demonstrated that the chemical synthesis of bacilotetrin C with suitable improvisation plays an important role in the development of novel anticancer chemotherapeutics, which would allow future rational design of novel autophagy inducers on this template.