Synthesis and biological activity of enantiomeric pairs of 5-vinylthiolactomycin congeners

Twelve enantiomeric pairs of 5-vinylthiolactomycin congeners were synthesized by employing our efficient synthetic route previously explored for the synthesis of enantiomeric pairs of thiolactomycin and its 3-demethyl derivative. From the biological activity assay carried out using the obtained congeners along with enantiomeric pairs of thiolactomycin and its 3-demethyl derivative previously prepared, it appeared evident that in vitro antibacterial and mammalian type I FAS inhibitory activity of thiolactomycin congeners can be cleanly separated by changing not only the structure but also the absolute configuration of the side chain at the C5-position. These studies led us to explore (S)-3-demethyl-5-(pent-1-enyl)thiolactomycin derivative [(S)-4-hydroxy-5-methyl-5-(pent-1-enyl)-5H-thiophen-2-one] which exhibits type I FAS inhibitory activity equal to that of C75, the potent inhibitor so far reported, with complete loss of in vitro antibacterial activity.

Graphical abstractAmong 3a–f, ent-3a–f, 4a–f, and ent-4a–f produced, (S)-3-demethyl-5-(pent-1-enyl)thiolactomycin derivative (ent-4d) exhibited mammalian type I FAS inhibitory activity equal to that of C75, the potent inhibitor so far reported, with complete loss of in vitro antibacterial activity.Figure optionsDownload full-size imageDownload as PowerPoint slide