(R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanenitrile | 1253736-46-7

• 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: (R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanenitrile
• 英文别名: 3α,7β-dihydroxy-5 β-cholane-24-nitrile；(4R)-4-[(3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanenitrile
• CAS: 1253736-46-7
• 化学式: C₂₄H₃₉NO₂
• 分子量: 373.579
• InChiKey: YAPWWCWTBOPUGG-ULQOMZCQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.96
• 拓扑面积：
  64.2
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanenitrile 在 sodium azide 、 碳酸氢钠 作用下， 以 水 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， 反应 7.0h， 生成 sodium 5-((R)-3-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethylhexadeca-hydro-1H-cyclopenta[a]phenanthren-17-yl)butyl)tetrazol-1-ide
  参考文献：
  名称：

  胆汁酸类似物抑制艰难梭菌芽孢萌发的合成及生物学评价

  摘要：

  基于标准抗生素的难治性梭状芽孢杆菌感染的治疗策略会破坏原生菌群，并且通常无法根除细菌孢子，这是导致感染复发的两个关键因素。作为控制艰难梭菌的替代方法感染后，已制备了一系列抑制牛磺胆酸盐诱导的孢子萌发的胆汁酸衍生物。这些类似物已使用光密度和相差显微镜分析法在高毒性NAP1菌株中进行了评估。在两种测定中，C24的杂环取代均具有良好的耐受性，几种含四唑的衍生物是高效抑制剂，在10–25μM时可完全抑制孢子萌发。为了限制肠道吸收，制备了旨在避免主动和被动转运途径的C7硫酸盐类似物。发现这些衍生物之一化合物21b是强效梭状芽胞杆菌的有效抑制剂。 Caco-2肠上皮吸收模型中的孢子萌发和渗透性差，表明它很可能受到肠道限制。

  DOI：

  10.1021/acs.jmedchem.7b00295
• 作为产物：
  描述：

  熊去氧胆酸 在 吡啶 、 氯化亚砜 、 高氯酸 、 氨 、 三氟乙酸酐 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 苯 为溶剂， 反应 28.33h， 生成 (R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanenitrile
  参考文献：
  名称：

  胆汁酸类似物抑制艰难梭菌芽孢萌发的合成及生物学评价

  摘要：

  基于标准抗生素的难治性梭状芽孢杆菌感染的治疗策略会破坏原生菌群，并且通常无法根除细菌孢子，这是导致感染复发的两个关键因素。作为控制艰难梭菌的替代方法感染后，已制备了一系列抑制牛磺胆酸盐诱导的孢子萌发的胆汁酸衍生物。这些类似物已使用光密度和相差显微镜分析法在高毒性NAP1菌株中进行了评估。在两种测定中，C24的杂环取代均具有良好的耐受性，几种含四唑的衍生物是高效抑制剂，在10–25μM时可完全抑制孢子萌发。为了限制肠道吸收，制备了旨在避免主动和被动转运途径的C7硫酸盐类似物。发现这些衍生物之一化合物21b是强效梭状芽胞杆菌的有效抑制剂。 Caco-2肠上皮吸收模型中的孢子萌发和渗透性差，表明它很可能受到肠道限制。

  DOI：

  10.1021/acs.jmedchem.7b00295

文献信息

• [EN] COMPOSITIONS AND METHODS FOR TREATING CLOSTRIDIUM ASSOCIATED DISEASES<br/>[FR] COMPOSITIONS ET MÉTHODES POUR LE TRAITEMENT DE MALADIES ASSOCIÉES À CLOSTRIDIUM
  申请人：UNIV MINNESOTA

  公开号：WO2017142895A8

  公开（公告）日：2017-10-19
• Bile acid toxicity structure–activity relationships: Correlations between cell viability and lipophilicity in a panel of new and known bile acids using an oesophageal cell line (HET-1A)
  作者：Ruchika Sharma、Ferenc Majer、Vijaya Kumar Peta、Jun Wang、Ray Keaveney、Dermot Kelleher、Aideen Long、John F. Gilmer

  DOI：10.1016/j.bmc.2010.07.030

  日期：2010.9

  The molecular mechanisms and interactions underlying bile acid cytotoxicity are important to understand for intestinal and hepatic disease treatment and prevention and the design of bile acid-based therapeutics.Bile acid lipophilicity is believed to be an important cytotoxicity determinant but the relationship is not well characterized. In this study we prepared new azido and other lipophilic BAs and altogether assembled a panel of 37 BAs with good dispersion in lipophilicity as reflected in RPTLC R-Mw. The MTT cell viability assay was used to assess cytotoxicity over 24 h in the HET-1A cell line (oesophageal). RMw values inversely correlated with cell viability for the whole set (r(2) = 0.6) but this became more significant when non-acid compounds were excluded (r(2) = 0.82, n = 29). The association in more homologous subgroups was stronger still (r(2) > 0.96). None of the polar compounds were cytotoxic at 500 mu M, however, not all lipophilic BAs were cytotoxic. Notably, apart from the UDCA primary amide, lipophilic neutral derivatives of UDCA were not cytotoxic. Finally, CDCA, DCA and LagoDCA were prominent outliers being more toxic than predicted by R-Mw. In a hepatic carcinoma line, lipophilicity did not correlate with toxicity except for the common naturally occurring bile acids and their conjugates. There were other significant differences in toxicity between the two cell lines that suggest a possible basis for selective cytotoxicity. The study shows: (i) azido substitution in BAs imparts lipophilicity and toxicity depending on orientation and ionizability; (ii) there is an inverse correlation between R-Mw and toxicity that has good predictive value in homologous sets; (iii) lipophilicity is a necessary but apparently not sufficient characteristic for BA cytocidal activity to which it appears to be indirectly related. (C) 2010 Elsevier Ltd. All rights reserved.
• COMPOSITIONS AND METHODS FOR TREATING CLOSTRIDIUM ASSOCIATED DISEASES
  申请人：KHORUTS Alexander

  公开号：US20200262865A1

  公开（公告）日：2020-08-20

  The present disclosure provides compounds for preventing, treating, and/or reducing the risk of developing a Clostridium -associated disease in a mammalian subject. Also provided are pharmaceutically acceptable salts of such compounds and compositions that include such compounds and/or pharmaceutically acceptable salts thereof.
• Synthesis and Biological Evaluation of Bile Acid Analogues Inhibitory to <i>Clostridium difficile</i> Spore Germination
  作者：Kristen L. Stoltz、Raymond Erickson、Christopher Staley、Alexa R. Weingarden、Erin Romens、Clifford J. Steer、Alexander Khoruts、Michael J. Sadowsky、Peter I. Dosa

  DOI：10.1021/acs.jmedchem.7b00295

  日期：2017.4.27

  bacterial spores, two key factors that allow recurrence of infection. As an alternative approach to controlling C. difficile infection, a series of bile acid derivatives have been prepared that inhibit taurocholate-induced spore germination. These analogues have been evaluated in a highly virulent NAP1 strain using optical density and phase-contrast microscopy assays. Heterocycle substitutions at C24 were

  基于标准抗生素的难治性梭状芽孢杆菌感染的治疗策略会破坏原生菌群，并且通常无法根除细菌孢子，这是导致感染复发的两个关键因素。作为控制艰难梭菌的替代方法感染后，已制备了一系列抑制牛磺胆酸盐诱导的孢子萌发的胆汁酸衍生物。这些类似物已使用光密度和相差显微镜分析法在高毒性NAP1菌株中进行了评估。在两种测定中，C24的杂环取代均具有良好的耐受性，几种含四唑的衍生物是高效抑制剂，在10–25μM时可完全抑制孢子萌发。为了限制肠道吸收，制备了旨在避免主动和被动转运途径的C7硫酸盐类似物。发现这些衍生物之一化合物21b是强效梭状芽胞杆菌的有效抑制剂。 Caco-2肠上皮吸收模型中的孢子萌发和渗透性差，表明它很可能受到肠道限制。