title: Novel P450(17alpha) inhibitors: 17-(2'-oxazolyl)- and 17-(2'-thiazolyl)-androstene derivatives.
abstract: Twelve 17-(2'-oxazolyl)- and 17-(2'-thiazolyl)-androsta-5,16-diene derivatives were designed and synthesized from 3 beta-acetoxy-pregna-5,16-dien-20-one (1b) as inhibitors of 17 alpha-hydroxylase-C(17,20)-lyase (P450(17 alpha)). Potent inhibitors of this enzyme could be of value as treatment of prostate cancer. Two substituents (methyl and phenyl) were introduced either at their 4'- or 5'-position in order to investigate their structure-activity relationship. Due to the 16,17-double bond, 17-thiazoles were generally obtained in low yield. The pharmacological results showed that the compounds containing 17-(2'-oxazolyl) (14c) and 17-(2'-thiazolyl) (8c) (41.5%) demonstrated reasonable inhibition against P450(17 alpha). Their 3-acetate (13c and 7c) were less potent than their 3-OH counterparts. The introduction of a phenyl or methyl group generally decreased inhibitory activity. Surprisingly, 17-(5'-methyl-2'-thiazolyl) (12a) was the most potent compound in this series and was almost as potent as L-39, which has good antitumor activity.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Center, Peking 100083, PR China.
authors.forename: Na
authors.initials: N
authors.lastname: Zhu
authors.forename: Yangzhi
authors.initials: Y
authors.lastname: Ling
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Lei
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Handratta
authors.forename: Angela M H
authors.initials: AM
authors.lastname: Brodie
mesh_terms: D000736:Androstenes / Q000138:chemical synthesis* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000736:Androstenes; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D013254:Steroid 17-alpha-Hydroxylase