title: Aromatic esters of progesterone as 5alpha-reductase and prostate growth inhibitors.
abstract: The aim of this study was to determine the biological activity of 4 steroidal derivatives (9a, 9b and 10a, 10b) prepared from the commercially available 17alpha acetoxyprogesterone, where 9a, 9b, have the Delta(4)-3-oxo structure and 10a and 10b an epoxy group at C-4 and C-5. These steroids were tested as inhibitors of 5alpha-reductase enzyme, which is present in androgen-dependent tissues and converts testosterone to its more active reduced metabolite dihydrotestosterone. The pharmacological effect of these steroids was demonstrated by the significant decrease of the weight of the prostate gland of gonadectomized hamsters treated with testosterone plus finasteride or with steroids 10a and 10b. For the studies in vitro the IC(50) values were determined by measuring the steroid concentration that inhibits 50% of the activity of-5alpha-reductase. In this study we also determined the capacity of these steroids to bind to the androgen receptor present in the rat prostate cytosol. The results from this work indicated that compounds 9a, 9b, 10a, and 10b inhibited the 5alpha reductase activity with IC(50) values of 360, 370, 13 and 4.9 nM respectively. However these steroids did not bind to the androgen receptors since none competed with labeled mibolerone. Steroid 10b, an epoxy steroidal derivative containing bromine atom in the ester moiety, was the most active inhibitor of 5alpha-reductase enzyme, present in human prostate homogenates with an IC(50) value of 4.9 nM and also showed in vivo pharmacological activity since it decreased the weight of the prostate from hamsters treated with testosterone in a similar way as finasteride.
authors.affiliation: Department of Pharmacy, Faculty of Chemistry, National University of Mexico City, Mexico D.F., Mexico.
authors.forename: Eugene
authors.initials: E
authors.lastname: Bratoeff
authors.forename: Tania
authors.initials: T
authors.lastname: Segura
authors.forename: Sergio
authors.initials: S
authors.lastname: Recillas
authors.forename: Eric
authors.initials: E
authors.lastname: Carrizales
authors.forename: Anay
authors.initials: A
authors.lastname: Palacios
authors.forename: Ivonne
authors.initials: I
authors.lastname: Heuze
authors.forename: Marisa
authors.initials: M
authors.lastname: Cabeza
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism; D058891:5-alpha Reductase Inhibitors; D000818:Animals; D001966:Bromine / Q000737:chemistry / Q000494:pharmacology; D006224:Cricetinae; D013196:Dihydrotestosterone / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D011374:Progesterone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011467:Prostate / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000378:metabolism; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000737:chemistry / Q000378:metabolism
chemical_list: D058891:5-alpha Reductase Inhibitors; D004791:Enzyme Inhibitors; D004952:Esters; D006131:Growth Inhibitors; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D013739:Testosterone; D011374:Progesterone; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D001966:Bromine