Aerab Abdul Karim , Atia-tul-Wahab , Ambreen Aziz , Nimra Naveed Shaikh , M. Iqbal Choudhary
{"title":"真菌对醋酸美替诺酮和表雄酮的生物转化及其对芳香酶抑制代谢产物的评价。","authors":"Aerab Abdul Karim , Atia-tul-Wahab , Ambreen Aziz , Nimra Naveed Shaikh , M. Iqbal Choudhary","doi":"10.1016/j.steroids.2023.109345","DOIUrl":null,"url":null,"abstract":"<div><p>The present study describes the microbial transformation of anabolic drugs, metenolone acetate (<strong>1</strong>), and epiandrosterone (<strong>6</strong>). Three new metabolites, 6<em>β,17β</em>-dihydroxy-1-methyl-3-oxo-5<em>α</em>-androst-1-en (<strong>2</strong>), 5<em>α</em>,15<em>α</em>-dihydroxy-1-methyl-3-oxo-1-en-17-yl acetate (<strong>3</strong>), 15<em>β</em>-hydroxy-1-methyl-3-oxo-5<em>α</em>-androst-1,4-dien-17-yl acetate (<strong>4</strong>), and a known metabolite, 17<em>β</em>-hydroxy-1-methyl-4-androstadiene-3-one (<strong>5</strong>) were obtained by biotransformation of metenolone acetate (<strong>1</strong>) <em>via Trametes hirsuta</em> mushroom. Metabolites <strong>7</strong>, and <strong>8</strong> were obtained from the incubation of epiandrosterone (<strong>6</strong>) with <em>Cunninghamella blakesleeana</em>. While bioconversion of compound <strong>6</strong> with <em>Aspergillus alliaceus</em> yielded seven known metabolites <strong>9</strong>–<strong>15</strong>. Modern spectroscopic techniques were employed for the structure elucidation of biotransformed products. All compounds were evaluated for their aromatase inhibitory activity. Among them, new metabolite <strong>3</strong> exhibited a significant human placental aromatase activity with an IC<sub>50</sub> = 19.602 ± 0.47 µM, as compared to standard anti-cancer drug exemestane (IC<sub>50</sub> = 0.232 ± 0.031 µM), whereas, metabolite <strong>5</strong> (IC<sub>50 =</sub> 0.0049 ± 0.0032 µM) exhibited a very potent activity. While substrate <strong>6</strong>, and metabolites <strong>2</strong>, <strong>7</strong>, and <strong>9</strong> were found inactive. Aromatase plays a key role in the biosynthesis of estrogen hormone, responsible for cancer cell proliferation. Its inhibition is therefore targeted for the treatment of ER + breast cancer. Further structural modifications (lead optimization) of compound <strong>3</strong> can lead to more potent aromatase inhibition for possible treatment of ER + breast cancer.</p></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":null,"pages":null},"PeriodicalIF":2.1000,"publicationDate":"2023-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Biotransformation of metenolone acetate and epiandrosterone by fungi and evaluation of resulting metabolites for aromatase inhibition\",\"authors\":\"Aerab Abdul Karim , Atia-tul-Wahab , Ambreen Aziz , Nimra Naveed Shaikh , M. Iqbal Choudhary\",\"doi\":\"10.1016/j.steroids.2023.109345\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>The present study describes the microbial transformation of anabolic drugs, metenolone acetate (<strong>1</strong>), and epiandrosterone (<strong>6</strong>). Three new metabolites, 6<em>β,17β</em>-dihydroxy-1-methyl-3-oxo-5<em>α</em>-androst-1-en (<strong>2</strong>), 5<em>α</em>,15<em>α</em>-dihydroxy-1-methyl-3-oxo-1-en-17-yl acetate (<strong>3</strong>), 15<em>β</em>-hydroxy-1-methyl-3-oxo-5<em>α</em>-androst-1,4-dien-17-yl acetate (<strong>4</strong>), and a known metabolite, 17<em>β</em>-hydroxy-1-methyl-4-androstadiene-3-one (<strong>5</strong>) were obtained by biotransformation of metenolone acetate (<strong>1</strong>) <em>via Trametes hirsuta</em> mushroom. Metabolites <strong>7</strong>, and <strong>8</strong> were obtained from the incubation of epiandrosterone (<strong>6</strong>) with <em>Cunninghamella blakesleeana</em>. While bioconversion of compound <strong>6</strong> with <em>Aspergillus alliaceus</em> yielded seven known metabolites <strong>9</strong>–<strong>15</strong>. Modern spectroscopic techniques were employed for the structure elucidation of biotransformed products. All compounds were evaluated for their aromatase inhibitory activity. Among them, new metabolite <strong>3</strong> exhibited a significant human placental aromatase activity with an IC<sub>50</sub> = 19.602 ± 0.47 µM, as compared to standard anti-cancer drug exemestane (IC<sub>50</sub> = 0.232 ± 0.031 µM), whereas, metabolite <strong>5</strong> (IC<sub>50 =</sub> 0.0049 ± 0.0032 µM) exhibited a very potent activity. While substrate <strong>6</strong>, and metabolites <strong>2</strong>, <strong>7</strong>, and <strong>9</strong> were found inactive. Aromatase plays a key role in the biosynthesis of estrogen hormone, responsible for cancer cell proliferation. Its inhibition is therefore targeted for the treatment of ER + breast cancer. Further structural modifications (lead optimization) of compound <strong>3</strong> can lead to more potent aromatase inhibition for possible treatment of ER + breast cancer.</p></div>\",\"PeriodicalId\":21997,\"journal\":{\"name\":\"Steroids\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.1000,\"publicationDate\":\"2023-11-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Steroids\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0039128X23001733\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Steroids","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0039128X23001733","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Biotransformation of metenolone acetate and epiandrosterone by fungi and evaluation of resulting metabolites for aromatase inhibition
The present study describes the microbial transformation of anabolic drugs, metenolone acetate (1), and epiandrosterone (6). Three new metabolites, 6β,17β-dihydroxy-1-methyl-3-oxo-5α-androst-1-en (2), 5α,15α-dihydroxy-1-methyl-3-oxo-1-en-17-yl acetate (3), 15β-hydroxy-1-methyl-3-oxo-5α-androst-1,4-dien-17-yl acetate (4), and a known metabolite, 17β-hydroxy-1-methyl-4-androstadiene-3-one (5) were obtained by biotransformation of metenolone acetate (1) via Trametes hirsuta mushroom. Metabolites 7, and 8 were obtained from the incubation of epiandrosterone (6) with Cunninghamella blakesleeana. While bioconversion of compound 6 with Aspergillus alliaceus yielded seven known metabolites 9–15. Modern spectroscopic techniques were employed for the structure elucidation of biotransformed products. All compounds were evaluated for their aromatase inhibitory activity. Among them, new metabolite 3 exhibited a significant human placental aromatase activity with an IC50 = 19.602 ± 0.47 µM, as compared to standard anti-cancer drug exemestane (IC50 = 0.232 ± 0.031 µM), whereas, metabolite 5 (IC50 = 0.0049 ± 0.0032 µM) exhibited a very potent activity. While substrate 6, and metabolites 2, 7, and 9 were found inactive. Aromatase plays a key role in the biosynthesis of estrogen hormone, responsible for cancer cell proliferation. Its inhibition is therefore targeted for the treatment of ER + breast cancer. Further structural modifications (lead optimization) of compound 3 can lead to more potent aromatase inhibition for possible treatment of ER + breast cancer.
期刊介绍:
STEROIDS is an international research journal devoted to studies on all chemical and biological aspects of steroidal moieties. The journal focuses on both experimental and theoretical studies on the biology, chemistry, biosynthesis, metabolism, molecular biology, physiology and pharmacology of steroids and other molecules that target or regulate steroid receptors. Manuscripts presenting clinical research related to steroids, steroid drug development, comparative endocrinology of steroid hormones, investigations on the mechanism of steroid action and steroid chemistry are all appropriate for submission for peer review. STEROIDS publishes both original research and timely reviews. For details concerning the preparation of manuscripts see Instructions to Authors, which is published in each issue of the journal.