Synthesis and biological activity of a novel 11a-homo (cyclohexyl) prostaglandin.
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 EC(50) value of 319 nM (72% response relative to cloprostenol); the corresponding values for PGF(2)(alpha) 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 alpha and omega chains and a new method for synthesis of aryloxy-terminated omega chains involving Horner-Emmons elongation of an aldehyde to a methyl enone, regioselective bromination adjacent to the carbonyl, and phenoxide displacement of bromide.
Klimko
P G
PG
Departments of Medicinal Chemistry and Molecular Pharmacology, Alcon Laboratories, Inc., 6201 South Freeway, MS R2-39, Ft. Worth, Texas 76134, USA. Peter.Klimko@Alconlabs.com
Davis
T L
TL
Griffin
B W
BW
Sharif
N A
NA
D016475:3T3 Cells; D000818:Animals; D003008:Cloprostenol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003338:Corpus Luteum / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000096:biosynthesis; D008024:Ligands; D051379:Mice; D011982:Receptors, Prostaglandin / Q000819:agonists* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C413887:16-(3-chlorophenoxy)-9,11a,15-trihydroxy-17,18,19,20-tetranor-11a-homo-5,13-prostadienoic acid; D007295:Inositol Phosphates; D008024:Ligands; D011982:Receptors, Prostaglandin; C034671:prostaglandin F2alpha receptor; D003008:Cloprostenol