17BETA-羟基-5ALPHA-雄甾烷-3,11-二酮 | 32694-37-4

• 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
• 中文名称: 17BETA-羟基-5ALPHA-雄甾烷-3,11-二酮
• 英文名称: 11-ketodihydrotestosterone
• 英文别名: 5α-androstan-17β-ol-3,11-dione；17β-Hydroxy-5α-androstan-3,11-dion；(5S,8S,9S,10S,13S,14S,17S)-17-hydroxy-10,13-dimethyl-2,4,5,6,7,8,9,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-3,11-dione
• CAS: 32694-37-4
• 化学式: C₁₉H₂₈O₃
• 分子量: 304.43
• InChiKey: RSQKILYTRHKUIJ-HZGXJFKTSA-N

物化性质

• 沸点：
  453.4±45.0 °C(Predicted)
• 密度：
  1.152±0.06 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  22
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.89
• 拓扑面积：
  54.4
• 氢给体数：
  1
• 氢受体数：
  3

制备方法与用途

生物活性

11-酮二氢睾酮（11-KDHT；5α-二氢-11-酮睾酮）是一种内源性类固醇，是11β-羟基雄烯二酮的代谢产物。11-KDHT 是一种活性雄激素，也是有效的雄激素受体 (AR) 激动剂，其对人 AR 的 Ki 值为 20.4 nM，EC50 值为 1.35 nM。在依赖雄激素的前列腺癌细胞中，11-KDHT 能诱导基因调节、蛋白质表达和细胞生长。

靶点

• Ki: 20.4 nM（人雄激素受体）
• EC50: 1.35 nM（人雄激素受体）

体外研究

在 LNCaP 和 VCaP 细胞中，使用 11-Ketodihydrotestosterone (11-KDHT；1-10 nM) 处理 24 小时，显著促进细胞增殖。在 LNCaP 和 VCaP 细胞中，用 11-KDHT（0.1-10 nM）处理 7-10 天后，观察到 KLK3、TMPRSS2 和 FKBP5 的显著上调，其中仅在 LNCaP 细胞中于 1 nM 浓度下未见 KLK3 上调。在 PNT2 细胞中，只有约 20% 的 11β-羟基雄烯二酮 (11OHA4) 和 11β-羟基睾酮 (11OHT) 被代谢，前者产生 11-酮-雄烯二酮 (11KA4)、11-KDHT 和 11β-羟基-5α-雄甾烯二酮 (11OH-5αDIONE)，后者则生成 11OHA4、11KT 及 11-KDHT，其下游产物浓度均低于 0.03 μM。在前列腺癌组织中，检测到 C11-氧 C19 代谢物的水平显著高于 C19 类固醇，未结合型 11-Ketodihydrotestosterone (11KT)、11OHA4 的浓度范围为 13 至 37.5 ng/g。在血浆中分析总类固醇水平显示 11OHA4（≈230-440 nM）、11KT（≈250-390 nM）和 11-Ketodihydrotestosterone（≈19 nM）的显著浓度。

细胞增殖测定

• 细胞系: LNCaP 和 VCaP 细胞
• 浓度: 0.1 nM, 1 nM 或 10 nM
• 孵育时间: LNCaP 细胞 7 天，VCaP 细胞 10 天
• 结果: 显著促进细胞增殖。

RT-PCR

• 细胞系: LNCaP 和 VCaP 细胞
• 浓度: 1 nM, 10 nM
• 孵育时间: 24 小时
• 结果: 在 LNCaP (图 3) 和 VCaP (图 4) 细胞中显著上调 KLK3、TMPRSS2 和 FKBP5。

反应信息

• 作为反应物：
  描述：

  17BETA-羟基-5ALPHA-雄甾烷-3,11-二酮 在 氧气 作用下， 生成 17β-Hydroxy-androstantrion-(3,4,11)
  参考文献：
  名称：

  Some Observations of Oxygenation of C<SUB>2</SUB>- or C<SUB>3</SUB>-Oxo-5α-steroids Possessing C<SUB>1</SUB>1-Oxo-group

  摘要：

  DOI：

  10.1248/cpb.12.1530
• 作为产物：
  描述：

  11 -酮睾酮 在 steroid 5α-reductase type 2 作用下， 生成 17BETA-羟基-5ALPHA-雄甾烷-3,11-二酮
  参考文献：
  名称：

  The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1

  摘要：

  Testosterone and its 5 alpha-reduced form, 5 alpha-dihydrotestosterone, were previously thought to represent the only active androgens in humans. However, recent studies have shown that the potent androgen, 11-ketotestosterone, derived from the adrenal androgen precursor, 110-hydroxyandrostenedione, may in fact serve as the primary androgen in healthy women. Yet, despite recent renewed interest in these steroids, their downstream metabolism has remained undetermined. We therefore set out to investigate the metabolism of 11-ketotestosterone by characterising the 5 alpha or 50-reduction commitment step. We show that inactivation of 11-ketotestosterone is predominantly driven by AKR1D1, which efficiently catalyses the 50-reduction of 11-ketotestosterone, committing it to a metabolic pathway that terminates in 11-ketoetiocholanolone. We demonstrate that 5 alpha-reduction of 11-ketotestosterone is catalysed by SRD5A2, but not SRD5A1, and terminates in 11-ketoandrosterone, but is only responsible for a minority of 11-ketotestosterone inactivation. However, as 11-ketoetiocholanolone is also generated by the metabolism of the glucocorticoid cortisone, 11-ketoandrosterone should be considered a more specific urinary marker of 11-ketotestosterone production.

  DOI：

  10.1016/j.jsbmb.2020.105724

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。
• Steroidal Thiazenones and Related Compounds¹
  作者：Philip E. Shaw、F. W. Gubitz、K. F. Jennings、G. O. Potts、A. L. Beyler、Robert L. Clarke

  DOI：10.1021/jm00334a034

  日期：1964.7
• Some Observations of Oxygenation of C&lt;SUB&gt;2&lt;/SUB&gt;- or C&lt;SUB&gt;3&lt;/SUB&gt;-Oxo-5α-steroids Possessing C&lt;SUB&gt;1&lt;/SUB&gt;1-Oxo-group
  作者：Shigekatsu Nakajima、Ken'ichi Takeda

  DOI：10.1248/cpb.12.1530

  日期：——
• The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1
  作者：Lise Barnard、Nikolaos Nikolaou、Carla Louw、Lina Schiffer、Hylton Gibson、Lorna C. Gilligan、Elena Gangitano、Jacky Snoep、Wiebke Arlt、Jeremy W. Tomlinson、Karl-Heinz Storbeck

  DOI：10.1016/j.jsbmb.2020.105724

  日期：2020.9

  Testosterone and its 5 alpha-reduced form, 5 alpha-dihydrotestosterone, were previously thought to represent the only active androgens in humans. However, recent studies have shown that the potent androgen, 11-ketotestosterone, derived from the adrenal androgen precursor, 110-hydroxyandrostenedione, may in fact serve as the primary androgen in healthy women. Yet, despite recent renewed interest in these steroids, their downstream metabolism has remained undetermined. We therefore set out to investigate the metabolism of 11-ketotestosterone by characterising the 5 alpha or 50-reduction commitment step. We show that inactivation of 11-ketotestosterone is predominantly driven by AKR1D1, which efficiently catalyses the 50-reduction of 11-ketotestosterone, committing it to a metabolic pathway that terminates in 11-ketoetiocholanolone. We demonstrate that 5 alpha-reduction of 11-ketotestosterone is catalysed by SRD5A2, but not SRD5A1, and terminates in 11-ketoandrosterone, but is only responsible for a minority of 11-ketotestosterone inactivation. However, as 11-ketoetiocholanolone is also generated by the metabolism of the glucocorticoid cortisone, 11-ketoandrosterone should be considered a more specific urinary marker of 11-ketotestosterone production.