{"title":"7-取代1,4,6-雄甾烯-3,17-二酮作为酶激活的不可逆芳香化酶抑制剂","authors":"Pui-Kai Li, Robert W. Brueggemeier","doi":"10.1016/0022-4731(90)90170-W","DOIUrl":null,"url":null,"abstract":"<div><p>7-Phenyl-1,4,6-androstatriene-3,17-dione (<strong>4</strong>), 7-benzyl-1,4,6-androstatriene-3,17-dione (<strong>5</strong>) and 7-phenethyl-1,4,6-androstatriene-3,17-dione (<strong>6</strong>) were synthesized and evaluated <em>in vitro</em> in human placental microsomes as enzyme-activated irreversible inhibitors of aromatase. The compounds were synthesized from appropriate 7-substituted 4,6-androstadiene-3, 17-diones by reaction with DDQ under neutral conditions. All the compounds produced a first order inactivation of aromatase in the presence of NADPH but not in the absence of NADPH. Substrate 4-androstene-3, 17-dione protected the enzyme from inactivation by the inhibitors. Furthermore, cysteine failed to protect aromatase from inactivation by compounds <strong>5</strong> and <strong>6</strong>. In contrast, cysteine partially protected aromatase from inactivation by compound <strong>4</strong>. Irreversibility studies illustrated the covalent nature of the inactivation by <strong>4</strong>, <strong>5</strong> and <strong>6</strong>. The above experimental evidence demonstrated that compounds <strong>5</strong> and <strong>6</strong> are effective enzyme-activated irreversible inhibitors of aromatase.</p></div>","PeriodicalId":17138,"journal":{"name":"Journal of steroid biochemistry","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"1990-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0022-4731(90)90170-W","citationCount":"19","resultStr":"{\"title\":\"7-Substituted 1,4,6-androstatriene-3,17-diones as enzyme-activated irreversible inhibitors of aromatase\",\"authors\":\"Pui-Kai Li, Robert W. Brueggemeier\",\"doi\":\"10.1016/0022-4731(90)90170-W\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>7-Phenyl-1,4,6-androstatriene-3,17-dione (<strong>4</strong>), 7-benzyl-1,4,6-androstatriene-3,17-dione (<strong>5</strong>) and 7-phenethyl-1,4,6-androstatriene-3,17-dione (<strong>6</strong>) were synthesized and evaluated <em>in vitro</em> in human placental microsomes as enzyme-activated irreversible inhibitors of aromatase. The compounds were synthesized from appropriate 7-substituted 4,6-androstadiene-3, 17-diones by reaction with DDQ under neutral conditions. All the compounds produced a first order inactivation of aromatase in the presence of NADPH but not in the absence of NADPH. Substrate 4-androstene-3, 17-dione protected the enzyme from inactivation by the inhibitors. Furthermore, cysteine failed to protect aromatase from inactivation by compounds <strong>5</strong> and <strong>6</strong>. In contrast, cysteine partially protected aromatase from inactivation by compound <strong>4</strong>. Irreversibility studies illustrated the covalent nature of the inactivation by <strong>4</strong>, <strong>5</strong> and <strong>6</strong>. The above experimental evidence demonstrated that compounds <strong>5</strong> and <strong>6</strong> are effective enzyme-activated irreversible inhibitors of aromatase.</p></div>\",\"PeriodicalId\":17138,\"journal\":{\"name\":\"Journal of steroid biochemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"1990-08-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1016/0022-4731(90)90170-W\",\"citationCount\":\"19\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of steroid biochemistry\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/002247319090170W\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of steroid biochemistry","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/002247319090170W","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
7-Substituted 1,4,6-androstatriene-3,17-diones as enzyme-activated irreversible inhibitors of aromatase
7-Phenyl-1,4,6-androstatriene-3,17-dione (4), 7-benzyl-1,4,6-androstatriene-3,17-dione (5) and 7-phenethyl-1,4,6-androstatriene-3,17-dione (6) were synthesized and evaluated in vitro in human placental microsomes as enzyme-activated irreversible inhibitors of aromatase. The compounds were synthesized from appropriate 7-substituted 4,6-androstadiene-3, 17-diones by reaction with DDQ under neutral conditions. All the compounds produced a first order inactivation of aromatase in the presence of NADPH but not in the absence of NADPH. Substrate 4-androstene-3, 17-dione protected the enzyme from inactivation by the inhibitors. Furthermore, cysteine failed to protect aromatase from inactivation by compounds 5 and 6. In contrast, cysteine partially protected aromatase from inactivation by compound 4. Irreversibility studies illustrated the covalent nature of the inactivation by 4, 5 and 6. The above experimental evidence demonstrated that compounds 5 and 6 are effective enzyme-activated irreversible inhibitors of aromatase.