Njar V C, Kato K, Nnane I P, Grigoryev D N, Long B J, Brodie A M
Department of Pharmacology & Experimental Therapeutics, School of Medicine, University of Maryland, Baltimore 21201, USA.
J Med Chem. 1998 Mar 12;41(6):902-12. doi: 10.1021/jm970568r.
A new synthetic route to a variety of novel delta 16-17-azolyl steroids is described: it involves the nucleophilic vinylic "addition-elimination" substitution reaction of 3 beta-acetoxy-17-chloro-16-formylandrosta-5,16-diene (2) and azolyl nucleophiles. Some of these novel delta 16-17-azolyl steroids, 6, 17, 19, and 27-29, prepared in good overall yields, are very potent inhibitors of human and rat testicular P450(17) alpha. They are shown to be noncompetitive and appear to be slow-binding inhibitors of human P450(17) alpha. The most potent compounds are 3 beta-hydroxy-17-(1H-imidazol-1-yl)androsta-5,16-diene (17), 3 beta-hydroxy-17-(1H-1,2,3-triazol-1-yl)androsta-5,-16-diene (19), and 17-(1H-imidazol-1-yl)androsta-4,16-dien-3-one (28), with Ki values of 1.2, 1.4, and 1.9 nM, respectively, being 20-32 times more potent than ketoconazole (Ki = 38 nM). Spectroscopic studies with a modified form of human P450(17) alpha indicate that the inhibition process involves binding of steroidal azole nitrogen to the heme iron of the enzyme. Furthermore, some of these potent P450(17) alpha inhibitors (27-29) are also powerful inhibitors of steroid 5 alpha-reductase, and others (17 and 19) appear to exhibit strong antiandrogenic activity in cultures of the LNCaP human prostatic cancer cell line. These novel compounds with impressive dual biological activities make them strong candidates for development as therapeutic agents for treatment of prostate cancer and other disease states which depend on androgens.
本文描述了一种合成多种新型δ16 - 17 - 氮杂甾体的新路线：该路线涉及3β - 乙酰氧基 - 17 - 氯 - 16 - 甲酰基雄甾 - 5,16 - 二烯（2）与氮杂环亲核试剂的亲核乙烯基“加成 - 消除”取代反应。以良好的总收率制备的一些新型δ16 - 17 - 氮杂甾体，如6、17、19和27 - 29，是人和大鼠睾丸P450(17)α的强效抑制剂。它们表现为非竞争性抑制剂，似乎是人类P450(17)α的慢结合抑制剂。最有效的化合物是3β - 羟基 - 17 -（1H - 咪唑 - 1 - 基）雄甾 - 5,16 - 二烯（17）、3β - 羟基 - 17 -（1H - 1,2,3 - 三唑 - 1 - 基）雄甾 - 5,16 - 二烯（19）和17 -（1H - 咪唑 - 1 - 基）雄甾 - 4,16 - 二烯 - 3 - 酮（28），其Ki值分别为1.2、1.4和1.9 nM，比酮康唑（Ki = 38 nM）的活性强20 - 32倍。对修饰形式的人类P450(17)α进行的光谱研究表明，抑制过程涉及甾体氮杂环与酶的血红素铁结合。此外，这些强效的P450(17)α抑制剂中的一些（27 - 29）也是甾体5α - 还原酶的强力抑制剂，而其他一些（17和19）在LNCaP人前列腺癌细胞系培养物中似乎表现出强大的抗雄激素活性。这些具有令人印象深刻的双重生物活性的新型化合物使其成为开发用于治疗前列腺癌和其他依赖雄激素的疾病状态的治疗药物的有力候选者。
