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.
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.
Vaddela Sudheer
VS
Babu
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.
Ya
Y
Zhou
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA. Electronic address: kishi@chemistry.harvard.edu.
Yoshito
Y
Kishi
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure
D000970:Antineoplastic Agents; D018942:Macrolides; C117218:mycolactone; C451489:mycolactone B
Buruli ulcer; Cytotoxicity; Dihydromycolactones; Mycolactones; Photochemical [(4)π(s)+(2)π(a)] cycloaddition