ABSTRACT
Suzuki coupling of 17-iodoandrosta-5,16-dien-3beta-ol (1) and 17-iodoandrosta-4,16-dien-3-one (2) with nine heteroaryl boronic acids (mainly 2- or 3-furanyl, thienyl, benzofuranyl and benzothienyl boronic acid derivatives) were carried out under normal Suzuki condition (Pd(PPh(3))(4), 2M Na(2)CO(3) and MeOH), generally yielded C(17)-heteroaryl steroids in moderate (10-60%) yields, but furanyl-2- and 5-chlorothienyl-2-boronic acid did not give any coupling product.
Subject(s)
Androstenes/chemical synthesis , Boronic Acids/chemistry , Palladium/chemistry , Androstenes/chemistry , Catalysis , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistryABSTRACT
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.
