3,4-dihydroxy-1,3,5(10),6,8-estrapentaen-17-one | 220997-45-5

• 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: 3,4-dihydroxy-1,3,5(10),6,8-estrapentaen-17-one
• 英文别名: 1,3,5(10),6,8-estrapentaen-2,3-diol-17-one；2-hydroxyequilenin；(13S,14S)-2,3-dihydroxy-13-methyl-12,14,15,16-tetrahydro-11H-cyclopenta[a]phenanthren-17-one
• CAS: 220997-45-5
• 化学式: C₁₈H₁₈O₃
• 分子量: 282.339
• InChiKey: INWCGRIZANYNHR-KSSFIOAISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  21
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 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：

  3,4-dihydroxy-1,3,5(10),6,8-estrapentaen-17-one 在 lithium tri-t-butoxyaluminum hydride 作用下， 生成 1,3,5(10),6,8-estrapentaen-2,3,17β-triol
  参考文献：
  名称：

  马来酸在MCF-7和MDA-MB-231人乳腺癌细胞中的代谢。

  摘要：

  B环不饱和雌激素，马匹林，马来宁和8-脱氢雌酮的硫酸盐共轭物及其17α-和17β-二氢类似物构成约54％的Premarin（Wyeth-Ayerst），这是雌激素替代中最常用的雌激素制剂治疗。尽管Premarin在临床上得到了广泛的应用，但是关于人类中B环不饱和雌激素代谢的研究很少，也没有关于这些化合物在乳腺组织或肿瘤中的命运的信息。在这项研究中，我们调查了人类乳腺癌细胞两系中MCF-7和MDA-MB-231中马鞭草素的代谢。MCF-7细胞对Ah受体激动剂的治疗有反应，诱导了细胞色素P450 1A1和1B1的诱导，而在MDA-MB-231细胞中，主要诱导了P450 1B1的诱导。利用一系列合成代谢物标准品和氘标记的类似物作为内标物，通过GC / MS鉴定并量化了马匹列宁的代谢物。在两种细胞系中，观察到相同的马匹素代谢途径。将马来酸在C-17还原为17β-二氢形式，同时最小化17α-二氢异构

  DOI：

  10.1021/tx000219r
• 作为产物：
  描述：

  马烯雌酮 在 copper dichloride selenium(IV) oxide 、 crown ether 、 碘 、 三溴化硼 、 维生素 C 作用下， 以 吡啶 、 甲醇 、 ammonium hydroxide 、 甲酸 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 叔丁醇 为溶剂， 反应 1.5h， 生成 3,4-dihydroxy-1,3,5(10),6,8-estrapentaen-17-one
  参考文献：
  名称：

  马雌激素代谢产物2-羟基马匹和2-羟基马匹的合成。

  摘要：

  Equilin和equilenin约占Premarin的20％，Premarin是目前最流行的雌激素替代疗法。尽管雌激素替代疗法有许多健康益处，但人们担心雌激素替代疗法与乳腺癌和子宫内膜癌的风险之间存在联系。雌激素致癌的一种潜在机理涉及雌激素代谢为2-和4-羟基邻苯二酚，其进一步被氧化为亲电/氧化还原活性邻醌，具有引发和促进致癌过程的潜力。在这项研究中，我们分别合成了雌马酚和雌马酚素，2-羟基Equilin和2-羟基Equilenin的潜在代谢物，以及它们的甲基醚代谢物。这些化合物是通过实用和有效的方法由市售的光学纯马鞭草素合成的。五个步骤得到了2-甲氧基e子苷，其中通过BBr3-催化的去甲基化在一个步骤中从中制备了2-羟基e子苷。类似地，用SeO2处理2-甲氧基表皮素，然后用BBr3脱甲基产生2-羟基表皮素。通过一维和二维NMR实验（包括1H，13C，APT，COSY，HMBC和HMQC

  DOI：

  10.1021/tx980189g

文献信息

• Synthesis of C-2 catecholic equilin and equilenin derivatives for use in metabolic studies.
  作者：SHIGEO IKEGAWA、TAKAO KUROSAWA、MASAHIKO TOHMA

  DOI：10.1248/cpb.36.2993

  日期：——

  In order to clarify the metabolic fate of equine estrogens, 2-hydroxyequilin, 2-hydroxy-equilenin and their isomeric monomethyl ethers were synthesized as authentic specimens. Vanillin and isovanillin were employed as starting materials leading to the desired β-ketosulfoxides (2a, b). Condensatin of the α, β-unsaturated ketones (4a, b) obtained by thermal elimination of 3a and 3b with 2-methylcyclopentane-1, 3-dione provided the triketones (5a, b), which were cyclized to the estrapentens (6a, b). Several oxido-reduction reactions were then performed to give the title compounds (8, 13).

  为了明确马雌激素的代谢命运，我们合成了 2-hydroxyequilin 和 2-hydroxy-equilenin 以及它们的异构单甲醚作为真实样本。以香兰素和异香兰素为起始原料，得到了所需的β-酮硫醚（2a、b）。用 2-甲基环戊烷-1, 3-二酮热消除 3a 和 3b 得到的 α, β-不饱和酮（4a, b）的缩合物提供了三酮（5a, b），三酮环化成酯戊烯（6a, b）。然后进行了几个氧化还原反应，得到了标题化合物（8、13）。
• Synthesis and Reactivity of the Catechol Metabolites from the Equine Estrogen, 8,9-Dehydroestrone
  作者：Fagen Zhang、Dan Yao、Yousheng Hua、Richard B. van Breemen、Judy L. Bolton

  DOI：10.1021/tx010049y

  日期：2001.6.1

  The risk factors for women developing breast and endometrial cancers are all associated with a lifetime of estrogen exposure. Estrogen replacement therapy in particular has been correlated with an increased cancer risk. Previously, we showed that the equine estrogens equilin and equilenin, which are major components of the widely prescribed estrogen replacement formulation Premarin, are metabolized to highly cytotoxic quinoids which caused oxidative stress and alkylation of DNA in vitro [Bolton, J. L., Pisha, E., Zhang, F., and Qiu, S. Chem. Res. Toxicol. 1998, 11, 1113-1127]. In this study, we have synthesized 8,9-dehydroestrone (a third equine estrogen component of Premarin) and its potential catechol metabolites, 4-hydroxy-8,9-dehydroestrone and 2-hydroxy-8,9-dehydroestrone. Both 2-hydroxy-8,9-dehydroestrone and 4-hydroxy-8,9-dehydroestrone were oxidized by tyrosinase or rat liver microsomes to o-quinones which reacted with GSH to give one mono-GSH conjugate and two di-GSH conjugates. Like endogenous estrogens, 8,9-dehydroestrone was primarily converted by rat liver microsomes to the 2-hydroxylated rather than the 4-hydroxylated o-quinone GSH conjugates; the ratio of 2-hydroxy-8,9-dehydroestrone versus 4-hydroxy-8,9-dehydroestrone was 6:1. Also in contrast to experiments with equilin, 4-hydroxyequilenin was not observed in microsomal incubations with 8,9-dehydroestrone or its catechols. The behavior of 2-hydroxy-8,9-dehydroestrone was found to be more complex than 4-hydroxy-8,9-dehydroestrone as GSH conjugates resulting from 2-hydroxy-8,9-dehydroestrone were detected even without oxidative enzyme catalysis. Under physiological conditions, 2-hydroxy-8,9-dehydroestrone isomerized to 8-hydroxyequilenin to form the very stable 2-hydroxyequilenin catechol; however, 4-hydroxy-8,9-dehydroestrone was found to be stable under similar conditions. Finally, preliminary studies conducted with the human breast tumor S-30 cell lines demonstrated that the catechol metabolites of 8,9-dehydroestrone were much less toxic than 4-hydroxyequilenin (20-40-fold). These results suggest that the catechol metabolites of 8,9-dehydroestrone may have the ability to cause cytotoxicity in vivo primarily through formation of o-quinones; however, most of the adverse effects of Premarin estrogens are likely due to formation of 4-hydroxyequilenin o-quinone from equilin and equilenin.
• JKEGAWA, SHIGEO;KUROSAWA, TAKAO;TOHMA, MASAHIKO, CHEM. AND PHARM. BULL., 36,(1988) N 8, C. 2993-2990
  作者：JKEGAWA, SHIGEO、KUROSAWA, TAKAO、TOHMA, MASAHIKO

  DOI：——

  日期：——
• Synthesis of the Equine Estrogen Metabolites 2-Hydroxyequilin and 2-Hydroxyequilenin
  作者：Fagen Zhang、Judy L. Bolton

  DOI：10.1021/tx980189g

  日期：1999.2.1

  Equilin and equilenin make up approximately 20% of Premarin which is currently the most popular estrogen replacement therapy. Although there are numerous health benefits of estrogen replacement therapy, there are concerns over the link between estrogen replacement therapy and breast and endometrial cancer risk. One potential mechanism of estrogen carcinogenesis involves metabolism of estrogens to 2-

  Equilin和equilenin约占Premarin的20％，Premarin是目前最流行的雌激素替代疗法。尽管雌激素替代疗法有许多健康益处，但人们担心雌激素替代疗法与乳腺癌和子宫内膜癌的风险之间存在联系。雌激素致癌的一种潜在机理涉及雌激素代谢为2-和4-羟基邻苯二酚，其进一步被氧化为亲电/氧化还原活性邻醌，具有引发和促进致癌过程的潜力。在这项研究中，我们分别合成了雌马酚和雌马酚素，2-羟基Equilin和2-羟基Equilenin的潜在代谢物，以及它们的甲基醚代谢物。这些化合物是通过实用和有效的方法由市售的光学纯马鞭草素合成的。五个步骤得到了2-甲氧基e子苷，其中通过BBr3-催化的去甲基化在一个步骤中从中制备了2-羟基e子苷。类似地，用SeO2处理2-甲氧基表皮素，然后用BBr3脱甲基产生2-羟基表皮素。通过一维和二维NMR实验（包括1H，13C，APT，COSY，HMBC和HMQC
• Metabolism of Equilenin in MCF-7 and MDA-MB-231 Human Breast Cancer Cells
  作者：David C. Spink、Fagan Zhang、Mirza M. Hussain、Barbara H. Katz、Xuemei Liu、David R. Hilker、Judy L. Bolton

  DOI：10.1021/tx000219r

  日期：2001.5.1

  same pathways of equilenin metabolism were observed. Equilenin was reduced at C-17 to the 17beta-dihydro form, with minimal production of the 17alpha-dihydro isomer. Both equilenin and 17beta-dihydroequilenin were hydroxylated at the C-4 position, and the resultant catechol metabolites were methylated to form 4-methoxyequilenin and 4-methoxy-17beta-dihydroequilenin. Rates of equilenin metabolism were

  B环不饱和雌激素，马匹林，马来宁和8-脱氢雌酮的硫酸盐共轭物及其17α-和17β-二氢类似物构成约54％的Premarin（Wyeth-Ayerst），这是雌激素替代中最常用的雌激素制剂治疗。尽管Premarin在临床上得到了广泛的应用，但是关于人类中B环不饱和雌激素代谢的研究很少，也没有关于这些化合物在乳腺组织或肿瘤中的命运的信息。在这项研究中，我们调查了人类乳腺癌细胞两系中MCF-7和MDA-MB-231中马鞭草素的代谢。MCF-7细胞对Ah受体激动剂的治疗有反应，诱导了细胞色素P450 1A1和1B1的诱导，而在MDA-MB-231细胞中，主要诱导了P450 1B1的诱导。利用一系列合成代谢物标准品和氘标记的类似物作为内标物，通过GC / MS鉴定并量化了马匹列宁的代谢物。在两种细胞系中，观察到相同的马匹素代谢途径。将马来酸在C-17还原为17β-二氢形式，同时最小化17α-二氢异构