Synthesis of 13,14-dehydroprostacyclin methyl ester: a potent inhibitor of platelet aggregation.
The structure of the most recently discovered, biologically highly active prostaglandin, PGI2 or prostacyclin, is correctly predicted on biogenetic grounds, and a general synthesis starting with prostaglandins of the F2alpha series is reported. Starting with the biologically active 13,14-dehydro-PGF2alpha, the synthesis involves formation of a 5-bromo-6,9alpha-epoxy derivative, followed by esterification and dehydrobromination of the methyl ester to form the prostacyclin structure. The stereochemistry at C-5 and C-6 of all reported products is assigned on the basis of experimental findings and mechanistic reasoning. 13,14-Dehydroprostacyclin methyl ester is considerably more stable at pH 7.5 than prostacyclin. It inhibits platelet aggregation induced by a variety of agents and causes an increase in renal blood flow in the dog at nanomolar levels.
D000818:Animals; D001681:Biological Assay; D004285:Dogs; D011464:Epoprostenol / Q000031:analogs & derivatives; D007536:Isomerism; D007668:Kidney / Q000098:blood supply; D009682:Magnetic Resonance Spectroscopy; D008722:Methods; D010974:Platelet Aggregation / Q000187:drug effects*; D011465:Prostaglandins, Synthetic / Q000138:chemical synthesis* / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects
D011465:Prostaglandins, Synthetic; C026435:13,14-dehydroprostaglandin I2 methyl ester; D011464:Epoprostenol
Biochemistry. 1971 Sep 28;10(20):3657-64
5096392
Proc Natl Acad Sci U S A. 1975 Aug;72(8):2994-8
1059088
J Am Chem Soc. 1976 Apr 14;98(8):2348-9
1254872
J Pharmacol Exp Ther. 1976 Jan;196(1):44-52
1246015
J Med Chem. 1973 Apr;16(4):429-30
4351914
Prostaglandins. 1976 Nov;12(5):685-713
824685
Nature. 1976 Oct 21;263(5579):663-5
802670
Adv Prostaglandin Thromboxane Res. 1976;1:183-93
998425
Prostaglandins. 1976 Dec;12(6):915-28
12538