17α,20α-dihydroxy-4-pregnen-3-one | 15959-00-9

• 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: 17α,20α-dihydroxy-4-pregnen-3-one
• 英文别名: 17α,20-dihydroxy-4-pregnen-3-one；17,20-Dihydroxypregn-4-en-3-one；(8R,9S,10R,13S,14S,17R)-17-hydroxy-17-(1-hydroxyethyl)-10,13-dimethyl-2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthren-3-one
• CAS: 15959-00-9
• 化学式: C₂₁H₃₂O₃
• 分子量: 332.483
• InChiKey: MASCESDECGBIBB-JAKCRWNRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  24
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.86
• 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：

  17α,20α-dihydroxy-4-pregnen-3-one 在 臭氧 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 生成 3-[(3R,3aS,5aS,6R,9aS,9bS)-3-Hydroxy-3-(1-hydroxy-ethyl)-3a,6-dimethyl-7-oxo-dodecahydro-cyclopenta[a]naphthalen-6-yl]-propionic acid
  参考文献：
  名称：

  氮杂类固醇作为大鼠前列腺5α-还原酶的抑制剂。

  摘要：

  已经制备了一系列A环杂环类固醇，并在体外测试了其对大鼠前列腺类固醇5α-还原酶的抑制作用。发现一组17个β-取代的4-甲基-4-氮杂-5α-雄甾烷-3-酮具有惊人的高抑制活性。这些化合物由3-酮-δ4前体通过氧化（O3或NaIO4-KMnO4）A环裂解，然后用胺闭环并在铂催化剂上氢化而制得。其他的A环氮杂甾类化合物是通过贝克曼重排2-oxo-A-nor，3-oxo-和4-oxo-5α-雄甾烷酮的肟制得的。通过用间氯过苯甲酸将前体2,3-二氧代-4-氮杂甾族化合物氧化脱羰制备A-正-2-氧代-3-氮杂甾族化合物。4-氮杂类固醇的A环修饰包括δ1-不饱和键，2-和4-取代基以及3-羰基取代基。

  DOI：

  10.1021/jm00378a028
• 作为产物：
  描述：

  17Alpha-羟基黄体酮 在 recombinant cDNA-expressed aldo-keto reductase (AKR₁C₁₂) potassium phosphate buffer 、 还原型辅酶II(NADPH)四钠盐 作用下， 生成 17α,20α-dihydroxy-4-pregnen-3-one
  参考文献：
  名称：

  Substrate Specificity of a Mouse Aldo-Keto Reductase (AKR1C12)

  摘要：

  AKR1C12是醛酮还原酶（AKR）超家族的小鼠成员，在胃中高表达，与小鼠髓系细胞中白细胞介素-3调控基因编码的蛋白相同，但其功能仍不清楚。本研究纯化了重组 AKR1C12，并在生理 pH 值为 7.4 的条件下检测了其对辅酶和底物的特异性。该酶以 NADH 为首选辅酶，还原了各种 α-二羰基化合物、几种类固醇、醛类和一些酮类化合物。在反向反应中，该酶表现出对 NAD+ 的辅酶偏好，可氧化 3α-、17β- 和 20α-羟基类固醇、非类固醇脂肪醇和脂环醇，其中许多羟基类固醇和香叶醇是良好的底物，表现出较低的 Km 值和较高的 kcat/Km 值。这些结果以及细胞内 NAD+/NADH 的高比率表明，AKR1C12 在小鼠胃和髓系细胞中发挥着内源性羟基类固醇和香叶醇脱氢酶的功能。

  DOI：

  10.1248/bpb.29.2488

文献信息

• Catalytic Hydroxylation of Olefins by Polymer-Bound Osmium Tetroxide
  作者：Gianfranco Cainelli、Michele Contento、Francesco Manescalchi、Laura Plessi

  DOI：10.1055/s-1989-27145

  日期：——

  Osmium tetroxide, linked to insoluble crosslinked polymers and copolymers bearing tertiary amino functions, has been used in the presence of secondary oxidants, such as hydrogen peroxide, tert-butyl hydroperoxide and trimethylamine N-oxide, to accomplish the catalytic hydroxylation of olefins. The polymeric reagent offers the advantages of easy and safe handling, and simple separation from the reaction medium. Generally good yields of vicinal diols have been obtained.

  四氧化锇与具有三级氨基功能的不可溶交联聚合物和共聚物相结合，在次级氧化剂（如过氧化氢、叔丁基过氧化氢和N-氧化三甲基胺）的 presence 中被用于催化烯烃的羟基化。聚合物试剂提供了易于安全操作和简单从反应介质中分离的优点。通常获得了较好的邻二醇产率。
• Structural requirements in 20-oxo-steroids for interaction with the catalytic site of 20.BETA.-hydroxysteroid dehydrogenase.
  作者：TAKAO HAYAKAWA、TSUYOSHI TANIMOTO、JIRO KAWAMURA

  DOI：10.1248/cpb.28.730

  日期：——

  Kinetic measurements were made to investigate the interaction of 20β-hydroxysteroid dehydrogenase and a series of steroids with C-17 and/or C-21 hydroxyl groups, and the role of the region around C-17 and C-21 on the interaction of the reacting 20-oxo group with the catalytic site of the enzyme was considered. Substitution of a hydroxyl group for hydrogen at C-21 of 17-deoxy-steroid derivatives caused a significant decrease in the apparent Vmax value (to about one-sixth to one-ninth), but a slight increase in the apparent Km value (about 1.1- to 1.8-fold). The same change at C-21 of 17-hydroxy-steroid derivatives caused little or no decrease in the apparent Vmax value, but an increase in the apparent Km (about 1.4- to 1.8-fold) occurred which was similar to that with 17-deoxy-steroid derivatives. In 21-deoxy-11-deoxy-steroid derivatives, a 17α-hydroxyl substituent had little effect on the apparent Km value (about 0.8- to 1.1-fold) and produced a slight decrease in the apparent Vmax value (to about three-quarters to two-fifths). Introduction of a 17α-hydroxyl group into 21-deoxy-11-oxo-steroid derivatives led to a significant decrease in the apparent Km value (to about one-seventh) and a moderate decrease in the apparent Vmax value (to about five-sixths to one-half). Introduction of a 17α-hydroxyl group into 21-hydroxy-steroid derivatives caused the apparent Vmax value to increase by about 1.8- to 11-fold, but caused little or no decrease in the apparent Km value. These results suggest that the hydroxyl group at the 21- or 17α-position directly restricted the conformation and the orientation of the 20-oxo group towards the catalytic site of the enzyme and influenced the hydrogen transfer stage in the catalytic process, and also that, of the substituents at the 21- and 17α-positions, the latter may preferentially affect the reaction efficiency of the 20-oxo group. The presence of an oxo group at C-11 had an indirect influence on the effects of the substituents at the 21- and 17α-positions. The optimum orientation of the 20-oxo group for the catalytic reaction may occur in 21-deoxy-17-deoxy-11-deoxy-steroid derivatives. In an ideal ternary complex, the 20-oxo group of the steroid may project towards the β-face of the steroid ring and the conformation between the 20-oxo group and α-hydrogen of C-17 is nearly staggered, while that between C-21 and the α-hydrogen of C-17, looking along the C-17 to C-20 axis, is in a skew form ; the 20-oxo group is orientated rather far from the methyl group at the β-position of C-13 and more towards the β-chain of C-16.

  进行了动力学测量，以研究20β-羟类固醇脱氢酶与一系列具有C-17和/或C-21羟基的类固醇之间的相互作用，并考虑了C-17和C-21附近区域对反应的20-氧基与酶催化位点相互作用的影响。将C-21的氢替换为羟基的17-脱氧类固醇衍生物导致表观Vmax值显著下降（降至约六分之一到九分之一），但表观Km值略微增加（约1.1到1.8倍）。在17-羟基类固醇衍生物的C-21处进行相同的改变对表观Vmax值几乎没有或没有造成下降，但表观Km值却增加（约1.4到1.8倍），这与17-脱氧类固醇衍生物的变化相似。在21-脱氧-11-脱氧类固醇衍生物中，17α-羟基取代体对表观Km值影响不大（约0.8到1.1倍），并导致表观Vmax值轻微下降（降至约三分之四到五分之二）。在21-脱氧-11-氧基类固醇衍生物中引入17α-羟基使表观Km值显著降低（降至约七分之一），而表观Vmax值中度下降（降至约五分之六到一半）。在21-羟基类固醇衍生物中引入17α-羟基使表观Vmax值增加约1.8到11倍，但对表观Km值几乎没有影响。这些结果表明，位于21或17α位点的羟基直接限制了20-氧基与酶催化位点之间的构象和取向，并影响了催化过程中的氢转移阶段。此外，在21和17α位点的取代基中，后者可能更优先影响20-氧基的反应效率。C-11的氧基的存在对21和17α位点取代基的影响具有间接作用。20-氧基在催化反应中的最佳取向可能发生在21-脱氧-17-脱氧-11-脱氧类固醇衍生物中。在一个理想的三元复合物中，类固醇的20-氧基可能朝向类固醇环的β面突出，且20-氧基与C-17的α-氢之间的构象几乎呈交错状态；而C-21与C-17的α-氢之间的角度在C-17至C-20轴上是倾斜的；20-氧基在空间上较远离C-13的β位甲基，更靠近C-16的β链。
• Relationship of human liver dihydrodiol dehydrogenases to hepatic bile-acid-binding protein and an oxidoreductase of human colon cells
  作者：Akira HARA、Kazuya MATSUURA、Yoshiyuki TAMADA、Kumiko SATO、Yoshiyuki MIYABE、Yoshihiro DEYASHIKI、Naoko ISHIDA

  DOI：10.1042/bj3130373

  日期：1996.1.15

  We previously isolated three monomeric dihydrodiol dehydrogenases, DD1, DD2 and DD4, from human liver, and cloned a cDNA (C9) thought to encode DD2, which is identical with those for human bile-acid-binding protein and an oxidoreductase of human colon carcinoma HT29 cells. In the present study we have provided evidence that the C9 cDNA clone encodes DD1, not DD2. A recombinant enzyme expressed from the cDNA in a bacterial system was purified, and its catalytic properties, bile-acid-binding ability and primary sequence were compared with those of the hepatic dihydrodiol dehydrogenases. The results show that DD1 encoded by C9 possesses prostaglandin F synthase activity but low affinity for lithocholic acid, whereas DD2, showing differences of six amino acid residues from the DD1 sequence, exhibited high-affinity binding for the bile acid. Refined relationship between dihydrodiol dehydrogenases and their related proteins of human tissues is proposed.

  我们之前从人类肝脏中分离出三种单体二氢二醇脱氢酶，DD1、DD2和DD4，并克隆了一个被认为编码DD2的cDNA（C9），该cDNA与人类胆酸结合蛋白和人类结肠癌HT29细胞的氧化还原酶相同。在本研究中，我们提供了证据表明C9 cDNA克隆编码的是DD1，而不是DD2。在细菌系统中表达的重组酶被纯化，并将其催化性质、胆酸结合能力和主要序列与肝脏二氢二醇脱氢酶进行了比较。结果表明，由C9编码的DD1具有前列腺素F合成酶活性，但对草酸胆碱的亲和力较低，而DD2与DD1序列有6个氨基酸残基的差异，表现出高亲和力的胆酸结合能力。提出了二氢二醇脱氢酶及其相关蛋白质在人类组织中的精细关系。
• Characterization of a human 20alpha-hydroxysteroid dehydrogenase
  作者：Y Zhang、I Dufort、P Rheault、V Luu-The

  DOI：10.1677/jme.0.0250221

  日期：2000.10.1

  It has been suggested that 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD) is a T-cell differentiation marker in mice. In the human, this enzyme has generally been associated with types 1 and 2 17beta-HSDs, which belong to the short-chain alcohol dehydrogenase family, whereas the rat, rabbit, pig and bovine 20alpha-HSDs are members of the aldoketo reductase superfamily, which also includes the 3alpha-HSD family. In this study, we report the cloning, from a human skin cDNA library, of a cDNA that shows, after transfection into human embryonic kidney (HEK-293) cells, high 20alpha-HSD activity but negligible 3alpha- and 17beta-hydroxysteroid dehydrogenase activities. A comparison of the amino acid sequence of the human 20alpha-HSD with those of other related 20alpha- and 3alpha-HSDs indicates that the human 20alpha-HSD shares 79.9, 68.7 and 52.3% identity with rabbit, rat and bovine 20alpha-HSDs, whereas it shows 97, 84 and 65% identity with human type 3, type 1 and rat 3alpha-HSDs. In contrast, the enzyme shares only 15.2 and 15.0% identity with type 1 and type 2 human 17beta-HSDs. DNA analysis predicts a protein of 323 amino acids, with a calculated molecular weight of 36 767 Da. In intact transfected cells, the human 20alpha-HSD preferentially catalyzes the reduction of progesterone to 20alpha-hydroxyprogesterone with a K(m) value of 0.6 microM, the reverse reaction (oxidation) being negligible. In a cell cytosolic preparation, the enzyme could use both NADPH and NADH as cofactors, but NADPH, which gave 4-fold lower K(m) values, was preferred. We detected the expression of 20alpha-HSD mRNA in liver, prostate, testis, adrenal, brain, uterus and mammary-gland tissues and in human keratinocyte (HaCaT) cells. The present study clearly indicates that the genuine human 20alpha-HSD belongs to the aldoketo reductase family, like the 20alpha-HSDs from other species.

  研究表明，20α-羟基类固醇脱氢酶（20α-HSD）是小鼠T细胞分化标记物。在人体内，该酶通常与1型和2型17β-HSDs相关，它们属于短链醇脱氢酶家族，而大鼠、兔子、猪和牛的20α-HSDs则属于醛酮还原酶超家族，该家族还包括3α-HSD家族。在本研究中，我们从人皮肤cDNA文库中克隆了一种cDNA，该cDNA在转染到人类胚胎肾（HEK-293）细胞后显示出高的20α-HSD活性，但3α-和17β-羟基类固醇脱氢酶活性微不足道。将人类20α-HSD的氨基酸序列与其他相关的20α-和3α-HSDs进行比较，结果显示人类20α-HSD与兔、大鼠和牛的20α-HSDs的相似性分别为79.9％、68.7％和52.3％，而与人类3α-HSDs、1型和大鼠3α-HSDs的相似性分别为97％、84％和65％。相比之下，该酶与1型和2型人类17β-HSDs的相似性仅为15.2％和15.0％。DNA分析预测该蛋白质由323个氨基酸组成，计算分子量为36,767 Da。在完整的转染细胞中，人类20α-HSD优先催化孕酮还原成20α-羟基孕酮，K(m)值为0.6微米，反应（氧化）微不足道。在细胞质制备中，该酶可以使用NADPH和NADH作为辅因子，但更喜欢NADPH，因为它给出4倍较低的K(m)值。我们检测到20α-HSD mRNA在肝脏、前列腺、睾丸、肾上腺、大脑、子宫和乳腺组织以及人类角质细胞（HaCaT）中的表达。本研究明确表明，真正的人类20α-HSD属于醛酮还原酶家族，类似于其他物种的20α-HSD。
• Antagonists of CB1 receptor
  申请人：INSERM (INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE)

  公开号：US10040816B2

  公开（公告）日：2018-08-07

  The invention relates to an antagonist of CB1 receptor for use in the treatment of a pathologic condition or disorder selected from the group consisting of bladder and gastrointestinal disorders; inflammatory diseases; cardiovascular diseases; nephropathies; glaucoma; spasticity; cancer; osteoporosis; metabolic disorders; obesity; addiction, dependence, abuse and relapse related disorders; psychiatric and neurological disorders; neurodegenerative disorders; autoimmune hepatitis and encephalitis; pain; reproductive disorders and skin inflammatory and fibrotic diseases.

  本发明涉及一种 CB1 受体拮抗剂，用于治疗选自以下组别的病理状况或紊乱：膀胱和胃肠道疾病；炎症性疾病；心血管疾病；肾病；青光眼；痉挛；癌症；骨质疏松症；代谢紊乱；肥胖；成瘾、依赖、滥用和复发相关紊乱；精神和神经紊乱；神经退行性疾病；自身免疫性肝炎；骨质疏松症；代谢紊乱；肥胖；成瘾、依赖、滥用和复发相关疾病；精神和神经系统疾病；神经退行性疾病；自身免疫性肝炎和脑炎；疼痛；生殖系统疾病以及皮肤炎症和纤维化疾病。