(3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3-((tert-butoxycarbonyl)amino)-10,13-dimethyl-17-((R)-5-oxopentan-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthrene-7,12-diyl diacetate | 1608486-90-3

• 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: (3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3-((tert-butoxycarbonyl)amino)-10,13-dimethyl-17-((R)-5-oxopentan-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthrene-7,12-diyl diacetate
• CAS: 1608486-90-3
• 化学式: C₃₃H₅₃NO₇
• 分子量: 575.786
• InChiKey: SLBDJWCQPLECGT-SJTFRAQVSA-N

物化性质

• 沸点：
  631.1±55.0 °C(predicted)
• 密度：
  1.12±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.24
• 重原子数：
  41.0
• 可旋转键数：
  7.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.88
• 拓扑面积：
  108.0
• 氢给体数：
  1.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  (3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3-((tert-butoxycarbonyl)amino)-10,13-dimethyl-17-((R)-5-oxopentan-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthrene-7,12-diyl diacetate 在 三乙酰氧基硼氢化钠 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 16.0h， 生成 24-N-methyl-N-[(7-chloroquinoline-4-yl)amino]propylamino-3α-amino-7α,12α-diacetoxy-5β-cholane
  参考文献：
  名称：

  Second Generation Steroidal 4-Aminoquinolines Are Potent, Dual-Target Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease andP. falciparumMalaria

  摘要：

  Significantly more potent second generation 4-amino-7-chloroquinoline (4,7-ACQ) based inhibitors of the botulinum neurotoxin serotype A (BoNT/A) light chain were synthesized. Introducing an amino group at the C(3) position of the cholate component markedly increased potency (IC50 values for such derivatives ranged from 0.81 to 2.27 mu M). Two additional subclasses were prepared: bis(steroidal)-4,7-ACQ derivatives and bis(4,7-ACQ)cholate derivatives; both classes provided inhibitors with nanomolar-range potencies (e.g., the K-i of compound 67 is 0.10 mu M). During BoNT/A challenge using primary neurons, select derivatives protected SNAP-25 by up to 89%. Docking simulations were performed to rationalize the compounds' in vitro potencies. In addition to specific residue contacts, coordination of the enzyme's catalytic zinc and expulsion of the enzyme's catalytic water were a consistent theme. With respect to antimalarial activity, the compounds provided better IC90 activities against chloroquine resistant (CQR) malaria than CQ, and seven compounds were more active than mefloquine against CQR strain W2.

  DOI：

  10.1021/jm500033r
• 作为产物：
  描述：

  3α-N-tert-butylcarbamate-7α,12α-diacetoxy-5β-cholanoic acid 在 氯甲酸乙酯 、 三乙胺 、 pyridinium chlorochromate 作用下， 以 二氯甲烷 为溶剂， 反应 7.75h， 生成 (3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3-((tert-butoxycarbonyl)amino)-10,13-dimethyl-17-((R)-5-oxopentan-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthrene-7,12-diyl diacetate
  参考文献：
  名称：

  Second Generation Steroidal 4-Aminoquinolines Are Potent, Dual-Target Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease andP. falciparumMalaria

  摘要：

  Significantly more potent second generation 4-amino-7-chloroquinoline (4,7-ACQ) based inhibitors of the botulinum neurotoxin serotype A (BoNT/A) light chain were synthesized. Introducing an amino group at the C(3) position of the cholate component markedly increased potency (IC50 values for such derivatives ranged from 0.81 to 2.27 mu M). Two additional subclasses were prepared: bis(steroidal)-4,7-ACQ derivatives and bis(4,7-ACQ)cholate derivatives; both classes provided inhibitors with nanomolar-range potencies (e.g., the K-i of compound 67 is 0.10 mu M). During BoNT/A challenge using primary neurons, select derivatives protected SNAP-25 by up to 89%. Docking simulations were performed to rationalize the compounds' in vitro potencies. In addition to specific residue contacts, coordination of the enzyme's catalytic zinc and expulsion of the enzyme's catalytic water were a consistent theme. With respect to antimalarial activity, the compounds provided better IC90 activities against chloroquine resistant (CQR) malaria than CQ, and seven compounds were more active than mefloquine against CQR strain W2.

  DOI：

  10.1021/jm500033r

文献信息

• New Steroidal 4-Aminoquinolines Antagonize Botulinum Neurotoxin Serotype A in Mouse Embryonic Stem Cell Derived Motor Neurons in Postintoxication Model
  作者：Jelena Konstantinović、Erkan Kiris、Krishna P. Kota、Johanny Kugelman-Tonos、Milica Videnović、Lisa H. Cazares、Nataša Terzić Jovanović、Tatjana Ž. Verbić、Boban Andjelković、Allen J. Duplantier、Sina Bavari、Bogdan A. Šolaja

  DOI：10.1021/acs.jmedchem.7b01710

  日期：2018.2.22

  The synthesis and inhibitory potencies against botulinum neurotoxin serotype A light chain (BoNT/A LC) using in vitro HPLC based enzymatic assay for various steroidal, benzothiophene, thiophene, and adamantane 4-aminoquinoline derivatives are described. In addition, the compounds were evaluated for the activity against BoNT/A holotoxin in mouse embryonic stem cell derived motor neurons. Steroidal derivative

  描述了使用基于体外HPLC的酶法测定各种甾体，苯并噻吩，噻吩和金刚烷4-氨基喹啉衍生物对A型肉毒杆菌神经毒素轻链（BoNT / A LC）的合成和抑制能力。另外，评估了化合物在小鼠胚胎干细胞衍生的运动神经元中对BoNT / A全毒素的活性。甚至在中毒后30分钟给药，类固醇衍生物16也显示出显着的保护作用（高达89％的未裂解SNAP-25）。这似乎是LC抑制剂在暴露后模型中拮抗小鼠胚胎干细胞衍生的运动神经元（mES-MNs）中BoNT中毒的第一个例子。口服16 高达600 mg / kg，qd的小鼠具有良好的耐受性，尽管在该剂量下未达到足够的未结合药物水平，但体外ADMET的良好结果有力地支持了该系列的进一步工作。