Synthesis and Biological Activity of a Novel 11a-Homo (Cyclohexyl) Prostaglandin

• Published in: Journal of medicinal chemistry 2000-09, Vol.43 (18), p.3400-3407
• Main Authors: Klimko, Peter G, Davis, Terry L, Griffin, Brenda W, Sharif, Najam A
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Alicyclic compounds, terpenoids, prostaglandins, steroids; Animals; Biological and medical sciences; Chemistry; Cloprostenol - analogs & derivatives; Cloprostenol - chemical synthesis; Cloprostenol - chemistry; Cloprostenol - pharmacology; Corpus Luteum - metabolism; Exact sciences and technology; Eye; Female; In Vitro Techniques; Inositol Phosphates - biosynthesis; Ligands; Medical sciences; Mice; Organic chemistry; Pharmacology. Drug treatments; Preparations and properties; Prostaglandins; Receptors, Prostaglandin - agonists; Receptors, Prostaglandin - metabolism; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm990587w

The racemic cyclohexane-for-cyclopentane ring substitution analogue of the potent prostaglandin FP agonist cloprostenol (7) was synthesized from cyclohexenediol 11 in 21 steps and 0.07% yield. In a prostaglandin FP receptor-linked second-messenger assay, racemic analogue 7 exhibited an EC50 value of 319 nM (72% response relative to cloprostenol); the corresponding values for PGF2 α and cloprostenol were 23 nM (91% relative response) and 1 nM (defined as 100% response), respectively. Key features of the synthesis were the selective manipulation of four hydroxyl groups to direct independent elaboration of the α and ω chains and a new method for synthesis of aryloxy-terminated ω chains involving Horner−Emmons elongation of an aldehyde to a methyl enone, regioselective bromination adjacent to the carbonyl, and phenoxide displacement of bromide.