Synthesis and biological testing of Acyl-CoA-ketoprofen conjugates as selective irreversible inhibitors of COX-2.
Ketoprofenoyl-CoA thioester 3 was synthesized by coupling ketoprofen to coenzyme A using the mixed anhydride method. Diastereoisomeric compounds 3a and 3b corresponding to the enantiomers of ketoprofen, were obtained in optically pure form by preparative HPLC. A non-acylating analogue, rac-3-(3-benzoylphenyl)-2-oxo-butanoyl-CoA (7) was also prepared. The biological evaluation suggested that 3a and 3b are reversible inhibitors of COX-1 and irreversible inhibitors of COX-2. Compound 7 appears to be a poor but selective inhibitor of COX-1.
Levoin
Nicolas
N
Unité Mixte 7561 CNRS-Université Henri Poincaré-Nancy 1, BP 187, F-54506 Nancy, Vandoeuvre, France.
Chrétien
Françoise
F
Lapicque
Françoise
F
Chapleur
Yves
Y
D000214:Acyl Coenzyme A / Q000737:chemistry* / Q000494:pharmacology; D000812:Anhydrides / Q000737:chemistry; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003432:Cross-Linking Reagents / Q000737:chemistry; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007660:Ketoprofen / Q000737:chemistry* / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases; D013329:Structure-Activity Relationship
D000214:Acyl Coenzyme A; D000812:Anhydrides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003432:Cross-Linking Reagents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007660:Ketoprofen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases