Synthesis and biological activity of carboxyl-terminus modified prostaglandin analogs

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Abstract
A series of PG[prostaglandin]E2, 16,16-dimethyl-PGE2 and PGF2.alpha. analogs modified at the carboxyl terminus with tetrazole, amide, acylurea, imide and sulfonimide functionalities was evaluated [in guinea pigs and mice] for uterine stimulant, bronchodilator, hypotensive, gastric antisecretory and diarrheal activity. These compounds were prepared by modification of the Corey PG synthesis utilizing as a key step condensation of known hemiacetals with the ylide derived from the requisite substituted phosphonium salts. Structure-activity relationships suggest that a proton at the C-1 position appears necessary for agonist activity and the acidity of this proton has a relatively greater influence on activity than pendant steric bulk. Noteworthy are the tissue-selective bronchodilator activity of N-acetyl-PGE2-carboxamide and the selectivity for uterine tissue of N-methanesulfonyl-PGE2-carboxamide, 2-decarboxy-2-(tetrazol-5-yl)-16,16-dimethyl-PGE2, N-acetyl-16,16-dimethyl-PGE2-carboxamide and N-methanesulfonyl-16,16-dimethyl-PGE2-carboxamide.