(1S,3aS,3bS,9aR,9bS,11aS)-1-Chlorocarbonyl-9a,11a-dimethyl-7-oxo-1,2,3,3a,3b,4,7,8,9,9a,9b,10,11,11a-tetradecahydro-cyclopenta[i]phenanthridine-5-carboxylic acid tert-butyl ester | 151520-69-3

• 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: (1S,3aS,3bS,9aR,9bS,11aS)-1-Chlorocarbonyl-9a,11a-dimethyl-7-oxo-1,2,3,3a,3b,4,7,8,9,9a,9b,10,11,11a-tetradecahydro-cyclopenta[i]phenanthridine-5-carboxylic acid tert-butyl ester
• 英文别名: tert-butyl (1S,3aS,3bS,9aR,9bS,11aS)-1-carbonochloridoyl-9a,11a-dimethyl-7-oxo-2,3,3a,3b,4,8,9,9b,10,11-decahydro-1H-cyclopenta[i]phenanthridine-5-carboxylate
• CAS: 151520-69-3
• 化学式: C₂₄H₃₄ClNO₄
• 分子量: 435.991
• InChiKey: OXDGVYKIXXUUMH-LBOBVIFKSA-N

物化性质

• 沸点：
  523.6±50.0 °C(predicted)
• 密度：
  1.21±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  30
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  63.7
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (1S,3aS,3bS,9aR,9bS,11aS)-1-Chlorocarbonyl-9a,11a-dimethyl-7-oxo-1,2,3,3a,3b,4,7,8,9,9a,9b,10,11,11a-tetradecahydro-cyclopenta[i]phenanthridine-5-carboxylic acid tert-butyl ester 在 三氟乙酸 作用下， 生成 (1S,3aS,3bS,9aR,9bS,11aS)-9a,11a-Dimethyl-7-oxo-2,3,3a,3b,4,5,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[i]phenanthridine-1-carboxylic acid tert-butylamide
  参考文献：
  名称：

  6-氮杂类固醇：人1型和2型类固醇5α-还原酶的有效双重抑制剂。

  摘要：

  DOI：

  10.1021/jm00078a022
• 作为产物：
  描述：

  17β-carboxy-6-(tert-butylcarboxy)-6-azaandrost-4-en-3-one 在 吡啶 、 氯化亚砜 、 N,N-二甲基甲酰胺 作用下， 以 甲苯 为溶剂， 反应 1.0h， 生成 (1S,3aS,3bS,9aR,9bS,11aS)-1-Chlorocarbonyl-9a,11a-dimethyl-7-oxo-1,2,3,3a,3b,4,7,8,9,9a,9b,10,11,11a-tetradecahydro-cyclopenta[i]phenanthridine-5-carboxylic acid tert-butyl ester
  参考文献：
  名称：

  [EN] AZASTEROIDS FOR TREATMENT OF TUBERCULOSIS
  [FR] COMPOSITION POUR LE TRAITEMENT DE LA TUBERCULOSE

  摘要：

  本发明提供了一种具有结构：式（I）的化合物，用于与抗结核药物结合，用于治疗感染结核分枝杆菌的受试者。

  公开号：

  WO2017190034A1

文献信息

• 6-Azasteroids: Structure-Activity Relationships for Inhibition of Type 1 and 2 Human 5.alpha.-Reductase and Human Adrenal 3.beta.-Hydroxy-.DELTA.5-steroid Dehydrogenase/3-Keto-.DELTA.5-steroid Isomerase
  作者：Stephen V. Frye、Curt D. Haffner、Patrick R. Maloney、Robert A. Mook、George F. Dorsey、Roger N. Hiner、Cindy M. Cribbs、Thomas N. Wheeler、John A. Ray

  DOI：10.1021/jm00041a014

  日期：1994.7

  6-Azaandrost-4-en-3-ones were synthesized and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-Delta(5)-steroid dehydrogenase/3-keto-Delta(5)-steroid isomerase (3BHSD) to explore the structure-activity relationship of this novel series in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Compounds with picomolar IC50's versus human type 2 5AR and low nanomolar K-i's versus human type 1 5AR with 100-fold selectivity versus 3BHSD were identified (70). Preliminary in vivo evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor-induced prostate involution and dog pharmacokinetic measurements identified a series of 17 beta-[N-(diphenylmethyl)carbamoyl]-6-azaandrost-4-en-3-ones (compounds 54, 66, and 67) with good in vivo efficacy and half-life in the dog. Inhibitors with, at the minimum, low nanomolar potency toward both human 5AR's and selectivity versus 3BHSD may show advantages over previously known 5AR inhibitors in the treatment of disease states which depend upon dihydrotestosterone, such as benign prostatic hyperplasia.
• Mce3R Stress-Resistance Pathway Is Vulnerable to Small-Molecule Targeting That Improves Tuberculosis Drug Activities
  作者：Xinxin Yang、Tianao Yuan、Rui Ma、Kieran I. Chacko、Melissa Smith、Gintaras Deikus、Robert Sebra、Andrew Kasarskis、Harm van Bakel、Scott G. Franzblau、Nicole S. Sampson

  DOI：10.1021/acsinfecdis.9b00099

  日期：2019.7.12

  One-third of the world's population carries Mycobacterium tuberculosis (Mtb), the infectious agent that causes tuberculosis (TB), and every 17 s someone dies of TB. After infection, Mtb can live dormant for decades in a granuloma structure arising from the host immune response, and cholesterol is important for this persistence of Mtb. Current treatments require long-duration drug regimens with many associated toxicities, which are compounded by the high doses required. We phenotypically screened 35 6-azasteroid analogues against Mtb and found that, at low micromolar concentrations, a subset of the analogues sensitized Mtb to multiple TB drugs. Two analogues were selected for further study to characterize the bactericidal activity of bedaquiline and isoniazid under normoxic and low-oxygen conditions. These two 6-azasteroids showed strong synergy with bedaquiline (fractional inhibitory concentration index = 0.21, bedaquiline minimal inhibitory concentration = 16 nM at 1 mu M 6-azasteroid). The rate at which spontaneous resistance to one of the 6-azasteroids arose in the presence of bedaquiline was approximately 10-9, and the 6-azasteroid-resistant mutants retained their isoniazid and bedaquiline sensitivity. Genes in the cholesterol-regulated Mce3R regulon were required for 6-azasteroid activity, whereas genes in the cholesterol catabolism pathway were not. Expression of a subset of Mce3R genes was down-regulated upon 6-azasteroid treatment. The Mce3R regulon is implicated in stress resistance and is absent in saprophytic mycobacteria. This regulon encodes a cholesterol-regulated stress-resistance pathway that we conclude is important for pathogenesis and contributes to drug tolerance, and this pathway is vulnerable to small-molecule targeting in live mycobacteria.