11β,17β-dihydroxy-5α-androstan-3-one | 7801-30-1

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: 11β,17β-dihydroxy-5α-androstan-3-one
• 英文别名: 11β,17β-dihydroxyandrostan-3-one；Androstan-3-one, 11,17-dihydroxy-, (5alpha,11beta,17beta)-；(5S,8S,9S,10S,11S,13S,14S,17S)-11,17-dihydroxy-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-one
• CAS: 7801-30-1
• 化学式: C₁₉H₃₀O₃
• 分子量: 306.445
• InChiKey: WARJRVLSUJRZKT-QHTZCDKYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  22
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.95
• 拓扑面积：
  57.5
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  11β,17β-dihydroxy-5α-androstan-3-one 在 盐酸 、 1,3-二溴-5,5-二甲基海因 、 偶氮二异丁腈 、 三正丁基氢锡 、 氟化氢吡啶 作用下， 以 甲醇 、 二氯甲烷 、 苯 为溶剂， 反应 10.5h， 生成 11beta-Fluoro-dihydrotestosterone
  参考文献：
  名称：

  Synthesis of 11.beta.-[18F]Fluoro-5.alpha.-dihydrotestosterone and 11.beta.-[18F]Fluoro-19-nor-5.alpha.-dihydrotestosterone: Preparation via Halofluorination-Reduction, Receptor Binding, and Tissue Distribution

  摘要：

  We have prepared 11 beta-fluoro-5 alpha-dihydrotestosterone (11 beta-F-DHT, 1) and 11 beta-fluoro-19-nor-5 alpha-dihydrotestosterone (11 beta-F-19-nor-DHT, 2) in order to investigate the properties of these new androgens labeled with fluorine-18 as potential androgen receptor (AR)-based imaging agents for prostate cancer. These compounds were synthesized in 6 steps from hydrocortisone and in 13 steps from 1,4-androstadiene-3,11,17-trione, respectively. Relative binding affinities (RBA) of 11 beta-F-DHT and 11 beta-F-19-nor-DHT to AR are 53.1 and 75.3 (R1881 = 100), respectively, the latter being the highest reported among fluorine-substituted androgens. The fluorination step, which involves addition of halogen fluoride across the 9(11)-double bond, followed by reductive dehalogenation at the 9 alpha-position has been adapted to introduce a fluorine-18-label at the 11 beta-position of DHT and 19-nor-DHT. The two high-affinity F-18-labeled ligands [F-18]-1 and [F-18]-2 were evaluated in vivo, in tissue distribution studies using diethylstilbestrol-pretreated mature male rats. 11 beta-F-DHT shows high prostate uptake and selective prostate to blood and prostate to muscle uptake ratios, the latter two ratios increasing from 5 and 8 at 1 h to 12 and 19 at 4 h postinjection. Moreover, this compound has low uptake in bone, displaying the lowest in vivo defluorination among all androgens labeled with fluorine-18 tested so far. The in vive properties of 11 beta-F-DHT in rats are thus favorable for imaging of prostate cancer. On the other hand, 11 beta-F-19-nor-DHT shows low prostate uptake with low selectivity and high uptake in liver, kidney, and bladder. Even though this ligand has the highest RBA and undergoes little metabolic defluorination, it appears to suffer from rapid metabolism in vivo. Therefore, it is apparent that the biodistribution properties of androgens are affected by their structure and metabolism as well as by their RBA.

  DOI：

  10.1021/jm00005a009
• 作为产物：
  描述：

  4-雄烯-11β-醇-3,17-二酮 在 氨 、 lithium 、 lithium tri-t-butoxyaluminum hydride 作用下， 以 四氢呋喃 为溶剂， 反应 4.25h， 生成 11β,17β-dihydroxy-5α-androstan-3-one
  参考文献：
  名称：

  Synthesis of 11.beta.-[18F]Fluoro-5.alpha.-dihydrotestosterone and 11.beta.-[18F]Fluoro-19-nor-5.alpha.-dihydrotestosterone: Preparation via Halofluorination-Reduction, Receptor Binding, and Tissue Distribution

  摘要：

  We have prepared 11 beta-fluoro-5 alpha-dihydrotestosterone (11 beta-F-DHT, 1) and 11 beta-fluoro-19-nor-5 alpha-dihydrotestosterone (11 beta-F-19-nor-DHT, 2) in order to investigate the properties of these new androgens labeled with fluorine-18 as potential androgen receptor (AR)-based imaging agents for prostate cancer. These compounds were synthesized in 6 steps from hydrocortisone and in 13 steps from 1,4-androstadiene-3,11,17-trione, respectively. Relative binding affinities (RBA) of 11 beta-F-DHT and 11 beta-F-19-nor-DHT to AR are 53.1 and 75.3 (R1881 = 100), respectively, the latter being the highest reported among fluorine-substituted androgens. The fluorination step, which involves addition of halogen fluoride across the 9(11)-double bond, followed by reductive dehalogenation at the 9 alpha-position has been adapted to introduce a fluorine-18-label at the 11 beta-position of DHT and 19-nor-DHT. The two high-affinity F-18-labeled ligands [F-18]-1 and [F-18]-2 were evaluated in vivo, in tissue distribution studies using diethylstilbestrol-pretreated mature male rats. 11 beta-F-DHT shows high prostate uptake and selective prostate to blood and prostate to muscle uptake ratios, the latter two ratios increasing from 5 and 8 at 1 h to 12 and 19 at 4 h postinjection. Moreover, this compound has low uptake in bone, displaying the lowest in vivo defluorination among all androgens labeled with fluorine-18 tested so far. The in vive properties of 11 beta-F-DHT in rats are thus favorable for imaging of prostate cancer. On the other hand, 11 beta-F-19-nor-DHT shows low prostate uptake with low selectivity and high uptake in liver, kidney, and bladder. Even though this ligand has the highest RBA and undergoes little metabolic defluorination, it appears to suffer from rapid metabolism in vivo. Therefore, it is apparent that the biodistribution properties of androgens are affected by their structure and metabolism as well as by their RBA.

  DOI：

  10.1021/jm00005a009

文献信息

• C11-hydroxy and C11-oxo C19 and C21 Steroids: Pre-Receptor Regulation and Interaction with Androgen and Progesterone Steroid Receptors
  作者：Rachelle Gent、Desmaré Van Rooyen、Stephen L. Atkin、Amanda C. Swart

  DOI：10.3390/ijms25010101

  日期：——

  C11-oxy C19 and C11-oxy C21 steroids have been identified as novel steroids but their function remains unclear. This study aimed to investigate the pre-receptor regulation of C11-oxy steroids by 11β-hydroxysteroid dehydrogenase (11βHSD) interconversion and potential agonist and antagonist activity associated with the androgen (AR) and progesterone receptors (PRA and PRB). Steroid conversions were investigated in transiently transfected HEK293 cells expressing 11βHSD1 and 11βHSD2, while CV1 cells were utilised for agonist and antagonist assays. The conversion of C11-hydroxy steroids to C11-oxo steroids by 11βHSD2 occurred more readily than the reverse reaction catalysed by 11βHSD1, while the interconversion of C11-oxy C19 steroids was more efficient than C11-oxy C21 steroids. Furthermore, 11-ketodihydrotestosterone (11KDHT), 11-ketotestosterone (11KT) and 11β-hydroxydihydrotestosterone (11OHDHT) were AR agonists, while only progestogens, 11β-hydroxyprogesterone (11βOHP4), 11β-hydroxydihydroprogesterone (11βOHDHP4), 11α-hydroxyprogesterone (11αOHP4), 11α-hydroxydihydroprogesterone (11αOHDHP4), 11-ketoprogesterone (11KP4), 5α-pregnan-17α-diol-3,11,20-trione (11KPdione) and 21-deoxycortisone (21dE) exhibited antagonist activity. C11-hydroxy C21 steroids, 11βOHP4, 11βOHDHP4 and 11αOHP4 exhibited PRA and PRB agonistic activity, while only C11-oxo steroids, 11KP4 and 11-ketoandrostanediol (11K3αdiol) demonstrated PRB agonism. While no steroids antagonised the PRA, 11OHA4, 11β-hydroxytestosterone (11OHT), 11KT and 11KDHT exhibited PRB antagonism. The regulatory role of 11βHSD isozymes impacting receptor activation is clear—C11-oxo androgens exhibit AR agonist activity; only C11-hydroxy progestogens exhibit PRA and PRB agonist activity. Regulation by the downstream metabolites of active C11-oxy steroids at the receptor level is apparent—C11-hydroxy and C11-oxo metabolites antagonize the AR and PRB, progestogens the former, androgens the latter. The findings highlight the intricate interplay between receptors and active as well as “inactive” C11-oxy steroids, suggesting novel regulatory tiers.

  C11-oxy C19 和 C11-oxy C21 类固醇已被确定为新型类固醇，但其功能仍不清楚。本研究旨在通过 11β- 羟类固醇脱氢酶（11βHSD）的相互转化以及与雄激素受体（AR）和孕激素受体（PRA 和 PRB）相关的潜在激动剂和拮抗剂活性，研究 C11-oxy 类固醇的前受体调节。在表达 11βHSD1 和 11βHSD2 的瞬时转染 HEK293 细胞中研究了类固醇的转化，并利用 CV1 细胞进行了激动剂和拮抗剂试验。与 11βHSD1 催化的逆反应相比，11βHSD2 更容易将 C11-hydroxy 类固醇转化为 C11-oxo 类固醇，而 C11-oxy C19 类固醇的相互转化比 C11-oxy C21 类固醇更有效。此外，11-酮二氢睾酮（11KDHT）、11-酮睾酮（11KT）和 11β-羟基二氢睾酮（11OHDHT）是 AR 激动剂，而只有孕激素、11β-羟基黄体酮（11βOHP4）、11β-羟基二氢黄体酮（11βOHDHP4）是 AR 激动剂、11α-羟基黄体酮（11αOHP4）、11α-羟基二氢黄体酮（11αOHDHP4）、11-酮黄体酮（11KP4）、5α-孕甾-17α-二醇-3,11,20-三酮（11KPdione）和 21-脱氧可的松（21dE）具有拮抗活性。C11-hydroxy C21 类固醇、11βOHP4、11βOHDHP4 和 11αOHP4 具有 PRA 和 PRB 激动活性，而只有 C11-oxo 类固醇、11KP4 和 11-ketoandrostanediol (11K3αdiol) 具有 PRB 激动活性。虽然没有类固醇能拮抗 PRA，但 11OHA4、11β-羟基睾酮（11OHT）、11KT 和 11KDHT 表现出 PRB 拮抗作用。影响受体激活的 11βHSD 同工酶的调节作用是明确的--11-氧代雄激素表现出 AR 激动剂活性；只有 C11-羟基孕激素表现出 PRA 和 PRB 激动剂活性。活性 C11-oxy 类固醇的下游代谢物在受体水平的调节作用显而易见--C11-羟基和 C11-oxo 代谢物可拮抗 AR 和 PRB，前者为孕激素，后者为雄激素。这些发现凸显了受体与活性以及 "非活性 "C11-氧类固醇之间错综复杂的相互作用，表明存在新的调节层。
• Synthesis of a precursor for the preparation of 9α, 11α-tritiated 5α-androstane-3α,17β-diol 17-glucuronide
  作者：P.Narasimha Rao、K.M. Damodaran

  DOI：10.1016/0039-128x(84)90052-7

  日期：1984.3

  Starting from 11 beta-hydroxytestosterone, we achieved the synthesis of a strategic precursor, C-9 (11) unsaturated 5 alpha-androstane-3 alpha, 17 beta-diol 17-glucuronide (9a), for the preparation of 9 alpha,11 alpha-tritiated 5 alpha-androstane-3 alpha, 17 beta-diol 17-glucuronide. We optimized the reaction conditions for catalytic reduction employing hydrogen and subsequent base hydrolysis followed by purification on Amberlite XAD-2 resin to obtain the saturated 5 alpha-androstane-3 alpha, 17 beta-diol 17-glucuronide.
• 11-SUBSTITUTED 24-HYDROXYSTEROLS FOR USE IN THE TREATMENT OF NMDA RELATED CONDITIONS
  申请人：Sage Therapeutics, Inc.

  公开号：EP3481846B1

  公开（公告）日：2021-05-12
• Treatment of myocardial infarction with 11HSD1 inhibitors
  申请人：Walker R. Brian

  公开号：US20080033046A1

  公开（公告）日：2008-02-07

  The present invention relates to a method for the treatment of myocardial infarction. In particular the invention relates to the treatment of myocardial infarction using inhibitors of a particular enzyme involved in glucocorticoid metabolism.
• Synthesis of 11.beta.-[18F]Fluoro-5.alpha.-dihydrotestosterone and 11.beta.-[18F]Fluoro-19-nor-5.alpha.-dihydrotestosterone: Preparation via Halofluorination-Reduction, Receptor Binding, and Tissue Distribution
  作者：Yearn Seong Choe、Pelle J. Lidstroem、Dae Yoon Chi、Thomas A. Bonasera、Michael J. Welch、John A. Katzenellenbogen

  DOI：10.1021/jm00005a009

  日期：1995.3

  We have prepared 11 beta-fluoro-5 alpha-dihydrotestosterone (11 beta-F-DHT, 1) and 11 beta-fluoro-19-nor-5 alpha-dihydrotestosterone (11 beta-F-19-nor-DHT, 2) in order to investigate the properties of these new androgens labeled with fluorine-18 as potential androgen receptor (AR)-based imaging agents for prostate cancer. These compounds were synthesized in 6 steps from hydrocortisone and in 13 steps from 1,4-androstadiene-3,11,17-trione, respectively. Relative binding affinities (RBA) of 11 beta-F-DHT and 11 beta-F-19-nor-DHT to AR are 53.1 and 75.3 (R1881 = 100), respectively, the latter being the highest reported among fluorine-substituted androgens. The fluorination step, which involves addition of halogen fluoride across the 9(11)-double bond, followed by reductive dehalogenation at the 9 alpha-position has been adapted to introduce a fluorine-18-label at the 11 beta-position of DHT and 19-nor-DHT. The two high-affinity F-18-labeled ligands [F-18]-1 and [F-18]-2 were evaluated in vivo, in tissue distribution studies using diethylstilbestrol-pretreated mature male rats. 11 beta-F-DHT shows high prostate uptake and selective prostate to blood and prostate to muscle uptake ratios, the latter two ratios increasing from 5 and 8 at 1 h to 12 and 19 at 4 h postinjection. Moreover, this compound has low uptake in bone, displaying the lowest in vivo defluorination among all androgens labeled with fluorine-18 tested so far. The in vive properties of 11 beta-F-DHT in rats are thus favorable for imaging of prostate cancer. On the other hand, 11 beta-F-19-nor-DHT shows low prostate uptake with low selectivity and high uptake in liver, kidney, and bladder. Even though this ligand has the highest RBA and undergoes little metabolic defluorination, it appears to suffer from rapid metabolism in vivo. Therefore, it is apparent that the biodistribution properties of androgens are affected by their structure and metabolism as well as by their RBA.