Synthesis and biological activity of prostaglandin lactones.
Most of the primary prostaglandins and several biologically important prostaglandin analogues were converted to 1,9-, 1,11- or 1,15-lactones, in order to investigate the biological profiles of these internal esters and to assess their potential as prodrugs for the corresponding open-chain hydroxy acids. In each case, the key lactonization step was done using Corey's "double activation" procedure (cyclization of omega-hydroxy-2-pyridinethiol esters). In general, the 1,9-lactones exhibited less than 1% of the biological activity of the parent hydroxy acids in the standard prostaglandin test systems. The 1,11- and 1,15-lactones, on the other hand, were essentially equal to the parent hydroxy acids as antifertility agents (a 4-day assay which would allow time for in vivo enzymatic lactone hydrolysis). The 1,11- and 1,15-lactones exhibited very low activity in acute or in vitro screens (e.g., rat blood pressure and gerbil colon stimulation), assays which more closely reflect the intrinsic activity of the lactones themselves. These results are consistent with the observed relative ease of enzymatic hydrolysis of the prostaglandin lactones (1,15 greater than or equal to 1,11 much greater than 1,9). Several of the lactones whose parent hydroxy acids are resistant to metabolic inactivation (e.g., 15-methyl, 16-phenoxy, and 17-phenyl) exhibited potent abortifacient activity in the hamster. These lactones, with greatly diminished activity in the blood pressure and smooth muscle assays (indicators of potential side effects), represent a therapeutically useful class of antifertility agents.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D003106:Colon / Q000187:drug effects; D006224:Cricetinae; D005260:Female; D005298:Fertility / Q000187:drug effects; D005849:Gerbillinae; D007783:Lactones / Q000138:chemical synthesis*; D008253:Macaca mulatta; D008297:Male; D011465:Prostaglandins, Synthetic / Q000138:chemical synthesis*; D051381:Rats
D007783:Lactones; D011465:Prostaglandins, Synthetic