Design, synthesis, and cytotoxicity of stabilized mycolactone analogs.

On exposure to visible light, mycolactone A/B, the causative toxin of Buruli ulcer, rearranges to a mixture of four photo-mycolactones apparently via a rare photochemically-induced [4πs+2πa] cycloaddition. In order to prevent the rearrangement, two C6'-C7' dihydromycolactone analogs 6'α-15 and 6'β-15 were designed and synthesized. 6'α-15 and 6'β-15 were shown to be stable under not only photochemical, but also acidic and basic conditions. Cytotoxicity was tested against arbitrarily chosen four cell lines (human Hek-293, human lung carcinoma A-549, human melanoma LOX-IMVI, and mouse L-929), thereby revealing that: (1) both analogs maintain potent cytotoxicity; (2) 6'β-15 exhibits significantly higher potency against human cell lines than 6'α-15; (3) in comparison with parent mycolactone A/B, 6'β-15 exhibits equal potency against human Hek-293, whereas significantly lower potency against human lung carcinoma A-549 and human melanoma LOX-IMVI.