Inhibition of platelet arachidonic acid 12-lipoxygenase by acetylenic acid compounds.

Eighteen acetylenic fatty acids were tested as inhibitors of human platelet arachidonic acid 12-lipoxygenase. 4,7,10,13-Eicosatetraynoic (4,7,10,13-ETYA) acid emerged as the most potent compound. Additional experiments have shown that 4,7,10,13-ETYA selectively blocked the 12-lipoxygenase in washed human platelets with lesser activity against the cyclooxygenase. The ID50 value for lipoxygenase was 7.8 microM in comparison with an ID50 of 100 microM for the cyclooxygenase. The commonly used inhibitor 5,8,11,14-eicosatetraynoic acid inhibited both enzymes with equal potency. It appears that 4,7,10,13-ETYA may be a valuable lead for selective modulation of the 12-lipoxygenase pathway in platelet or other target tissues.

The stability of 13,14-dihydro-15 keto-PGE2.

13,14-Dihydro-15 keto-PGE2 decomposes by first order reaction kinetics, dependent on pH, temperature and albumin concentration. Under common experimental conditions at or near neutrality in the absence of albumin decomposition is suspended with the formation of 13,14-dihydro-15-keto-PGA2. Cyclization into 11-deoxy-13,14-dihydro-15 keto-11,16-bicyclo-PGE2 occurs at elevated pH in purely aqueous buffers, and also at or near neutrality in the presence of albumin. Albumin accelerates, quantitatively, the decomposition of 13,14-dihydro-15 keto-PGE2 and promotes, qualitatively, the formation of the bicyclo rearrangement product. High performance liquid chromatographic analysis indicates that the cyclization product exists in at least three epimerically distinct forms. The two major epimers have been synthesized and isolated in pure form. They differ, mainly, by their optical rotation.

Total synthesis of prostaglandins.

PIP: Prostaglandins, a family of naturally occurring hydroxy fatty acids found widely distributed in mammalian tissues, have been found to have a wide potential in medical use. The need to synthesize these substances for study, first, and, later, for production and distribution prompted this review of the various methods for chemical synthesis of these compounds. Following a general introduction, this review presents 6 major chapters: 1) the structure and chemical transformations of prostaglandins; 2) general approaches to prostaglandin synthesis (these include initial Corey synthesis of dl-PGE1, Corey's second synthesis of dl-PGE1, a stereocontrolled synthesis of PGE2 and F2 alpha, also by Corey's methods, bicyclohexane route to prostaglandins, and nonenzyme cyclization of fatty acids), 3) synthetic routes to structurally simplified prostaglandins (synthesis of dl-13,14-dihydro-PGE1 ethyl ester, synthesis of dl-15-dehydro-PGE1, and synthesis of dl-PGB1); 4) synthetic routes to prostaglandin analogs (11-deoxy-prostaglandins and 7-oxa-prostaglandins); 5) miscellaneous synthetic approaches; and 6) resolution of racemic prostaglandins.^ieng

The synthesis of prostaglandin E1 and related substances.

PIP: The authors describe in detail the conversion of 4 isometric exo-substituted bicyclo (3.1.0) hexanones 1a, 1b, 2a and 2b (R=CH3) to 4 prostaglandins of the E series, including crystalline dl-prostaglandin E1 (PGE1). Oxidative solvolysis of the keto esters 1a and 2a and of the desired keto acids 1a and 2a (R=H) according to the method of Just and Simonovitch resulted in a good yield of the mixture of vic-glycols of unrearranged carbon skeleton. The presence of dl-PGE1, or dl-8-iso PGE1 or their methyl esters was not detected in either case. Analysis of the unalkylated ketones 5a and 5b under the same and other conditions yielded unrearranged vic-glycols 6 as essentially the only product. A reaction sequence produced dl-8-isoprostaglandin E1, the 15-epimers of these prostaglandins, and dl-PGA1 and dl-PGB1 methyl esters.^ieng