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 C(5)-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.
Ohata
Kohei
K
Kyorin Pharmaceutical Co., Ltd., Discovery Research Laboratories, 2399-1 Nogi, Nogi-Machi, Shimotsuga, Tochigi 329-0114, Japan. oohata@mb.kyorin-pharm.co.jp
Terashima
Shiro
S
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D013876:Thiophenes; D064429:Fatty Acid Synthases