Synthesis of biologically active dicarba analogues of the peptide hormone oxytocin using ring-closing metathesis.
Facile synthesis of cis and trans olefinic analogues of oxytocin 1 that have carbon in place of sulfur is achieved via ring-closing metathesis (RCM) on a resin-bound linear precursor peptide. Hydrogenation of the cis olefin, 3, proceeds selectively to generate the previously reported saturated derivative 5. Biological testing on rat uterus strips shows that cis compound 3 has an EC50 value of 38 ng/mL (EC50 for oxytocin is 2.7 ng/mL) whereas 5 and trans olefin 4 are less active. [reaction--see text]
Stymiest
Jake L
JL
Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada, T6G 2G2.
Mitchell
Bryan F
BF
Wong
Susan
S
Vederas
John C
JC
D000818:Animals; D005260:Female; D006865:Hydrogenation; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010121:Oxytocin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D014599:Uterus / Q000187:drug effects / Q000502:physiology
D010121:Oxytocin