Total synthesis and comparative analysis of orlistat, valilactone, and a transposed orlistat derivative: Inhibitors of fatty acid synthase.
Concise syntheses of orlistat (Xenical), a two-carbon transposed orlistat derivative, and valilactone are described that employ the tandem Mukaiyama aldol-lactonization (TMAL) process as a key step. This process allows facile modification of the alpha-side chain. Versatile strategies for modifying the delta-side chain are described, involving cuprate addition and olefin metathesis. Comparative antagonistic activity of these derivatives toward a recombinant form of the thioesterase domain of fatty acid synthase is reported along with comparative activity-based profiling.
Ma
Gil
G
Department of Chemistry, Texas A&M University, College Station, Texas 77842-3012, USA.
Zancanella
Manuel
M
Oyola
Yatsandra
Y
Richardson
Robyn D
RD
Smith
Jeffrey W
JW
Romo
Daniel
D
D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis* / Q000494:pharmacology; D000077403:Orlistat; D013237:Stereoisomerism
D019440:Anti-Obesity Agents; D004791:Enzyme Inhibitors; D007783:Lactones; C054478:valilactone; D000077403:Orlistat; D064429:Fatty Acid Synthases