Synthesis and biological activity of enantiomeric pairs of 5-(Alk-2-enyl)thiolactomycin and 5-[(E)-Cycloalk-2-enylidenemethyl]thiolactomycin congeners.
The title compounds were synthesized by the efficient route previously explored for the synthesis of enantiomeric pairs of thiolactomycin and its 3-demethyl derivative. These studies were carried out to prove the flexibility of the previously explored synthetic route to natural thiolactomycin (TLM) 1 and to examine the structure-activity relationship on the 5-position of 1. While all of the synthesized congeners lacked in vitro antibacterial activity, these studies led us to find 5-(alk-2-enyl)-TLM (ent-4d) which exhibits mammalian type I fatty acid synthase (FAS) inhibitory activity equal to that of C75, a potent inhibitor reported previously. It was also found that 5-[(E)-cycloalk-2-enylidenemethyl]-TLM (ent-5c) exhibited slightly less potent mammalian type I FAS inhibitory activity than C75.
Ohata
Kohei
K
Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd, Japan. kouhei.oohata@mb.kyorin-pharm.co.jp
Terashima
Shiro
S
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000378:metabolism; D054872:Fatty Acid Synthesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D054872:Fatty Acid Synthesis Inhibitors; D013876:Thiophenes; C035068:thiolactomycin; D064429:Fatty Acid Synthases