S-[2-[(2-ethylphenyl)amino]-2-oxoethyl] [2-[(2S)-3-(1H-indol-3-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]hydrazinyl]methanethioate | 958772-66-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: S-[2-[(2-ethylphenyl)amino]-2-oxoethyl] [2-[(2S)-3-(1H-indol-3-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]hydrazinyl]methanethioate
• 英文别名: N-[(1,1-dimethylethoxy)carbonyl]-L-tryptophan-2-[[[2-[(2-ethylphenyl)amino]-2-oxoethyl]thio]carbonyl]hydrazide；SID 26681509；tert-butyl N-[(2S)-1-[2-[2-(2-ethylanilino)-2-oxoethyl]sulfanylcarbonylhydrazinyl]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]carbamate
• CAS: 958772-66-2
• 化学式: C₂₇H₃₃N₅O₅S
• 分子量: 539.656
• InChiKey: OTIWAYTTYNFEKL-QFIPXVFZSA-N

物化性质

• 熔点：
  131 °C
• 密度：
  1.298±0.06 g/cm3(Predicted)
• 溶解度：
  <26.98mg/ml，溶于 DMSO； <5.4mg/ml，在乙醇中

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  38
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  167
• 氢给体数：
  5
• 氢受体数：
  6

安全信息

• 储存条件：
  -20°C，干燥密封

制备方法与用途

生物活性

SID 26681509 是一种有效的、可逆的竞争性选择性人组织蛋白酶 L（human cathepsin L）抑制剂，IC50 值为 56 nM。它能有效抑制疟原虫 (Plasmodium falciparum) 和利什曼原虫 (Leishmania major)，其 IC50 分别为 15.4 μM 和 12.5 μM。然而，SID 26681509 对组织蛋白酶 G 没有抑制活性。

靶点

• IC50: 人组织蛋白酶 L (56 nM), 组织蛋白酶 V (0.5 μM), 疟原虫 (Plasmodium falciparum) (15.4 μM), 利什曼原虫 (Leishmania major) (12.5 μM)

体外研究

在与组织蛋白酶 L 预孵育 4 小时后，SID 26681509 的效果增强，IC50 值降至 1.0 nM。研究表明该化合物是一种慢结合且缓慢可逆的竞争性抑制剂。通过瞬态动力学分析得出单步可逆抑制的速率常数为 kon = 24,000 M⁻¹ s⁻¹ 和 koff = 2.2 × 10⁻⁵ s⁻¹ (Ki = 0.89 nM)。

分子对接研究使用了 papain/CLIK-148 的实验晶体结构。SID 26681509 对 papain 及组织蛋白酶 B、K、S 和 V 的 IC50 值在预孵育 1 小时后分别为 618 nM 至 8.442 μM，对组织蛋白酶 G 没有抑制活性。它还显示出对组织蛋白酶 V 的 IC50 值为 0.5 μM。

研究表明，SID 26681509 (1-30 μM) 能剂量依赖性地阻断高移动性组盒 1（HMGB1）诱导的 TNF-α 生产而不影响细胞活力。

体内研究

在小鼠脓毒症模型中，SID 26681509 治疗显著提高了存活率，并减少了暖肝缺血再灌注 (I/R) 模型中的肝脏损伤。

反应信息

• 作为反应物：
  描述：

  S-[2-[(2-ethylphenyl)amino]-2-oxoethyl] [2-[(2S)-3-(1H-indol-3-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]hydrazinyl]methanethioate 在 三氟乙酸 作用下， 反应 0.33h， 以98%的产率得到S-[2-(2-ethylanilino)-2-oxoethyl] N-[[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino]carbamothioate
  参考文献：
  名称：

  Identification and synthesis of a unique thiocarbazate cathepsin L inhibitor

  摘要：

  Library samples containing 2,5-disubstituted oxadiazoles were identified as potent hits in a high throughput screen (HTS) of the NIH Molecular Libraries Small Molecule Repository (MLSMR) directed at discovering inhibitors of cathepsin L. However, when synthesized in pure form, the putative actives were found to be devoid of biological activity. Analyses by LC-MS of original library samples indicated the presence of a number of impurities, in addition to the oxadiazoles. Synthesis and bioassay of the probable impurities led to the identification of a thiocarbazate that likely originated via ring opening of the oxadiazole. Previously unknown, thiocarbazates (-)-11 and (-)-12 were independently synthesized as single enantiomers and found to inhibit cathepsin L in the low nanomolar range. (C) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.10.107
• 作为产物：
  描述：

  [[(2S)-3-(1H-indol-3-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]carbamothioic S-acid 、 N-(2-ethylphenyl)carbamoyl bromide 以 乙醇 为溶剂， 反应 1.0h， 生成 S-[2-[(2-ethylphenyl)amino]-2-oxoethyl] [2-[(2S)-3-(1H-indol-3-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]hydrazinyl]methanethioate
  参考文献：
  名称：

  Design, synthesis, and evaluation of inhibitors of cathepsin L: Exploiting a unique thiocarbazate chemotype

  摘要：

  Recently, we identified a thiocarbazate that exhibits potent inhibitory activity against human cathepsin L. Since this structure represents a novel chemotype with potential for activity against the entire cysteine protease family, we designed, synthesized, and assayed a series of analogs to probe the mechanism of action, as well as the structural requirements for cathepsin L activity. Molecular docking studies using coordinates of a papain-inhibitor complex as a model for cathepsin L provided useful insights. (C) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2008.04.065

文献信息

• Design, Synthesis and Biological Evaluation of a Library of Thiocarbazates and Their Activity as Cysteine Protease Inhibitors
  作者：Zhuqing Liu、Michael C. Myers、Parag P. Shah、Mary Pat Beavers、Phillip A. Benedetti、Scott L. Diamond、Amos B. Smith,III、Donna M. Huryn

  DOI：10.2174/138620710791054303

  日期：2010.5.1

  Recently, we identified a novel class of potent cathepsin L inhibitors, characterized by a thiocarbazate warhead. Given the potential of these compounds to inhibit other cysteine proteases, we designed and synthesized a library of thiocarbazates containing diversity elements at three positions. Biological characterization of this library for activity against a panel of proteases indicated a significant preference for members of the papain family of cysteine proteases over serine, metallo-, and certain classes of cysteine proteases, such as caspases. Several potent inhibitors of cathepsin L and S were identified. The SAR data were employed in docking studies in an effort to understand the structural elements required for cathepsin S inhibition. This study provides the basis for the design of highly potent and selective inhibitors of the papain family of cysteine proteases.

  最近，我们鉴定出一类新型高效组织蛋白酶L抑制剂，其特点是具有硫卡巴脒头部结构。鉴于这些化合物有可能抑制其他半胱氨酸蛋白酶，我们设计并合成了一系列硫卡巴脒类化合物，这些化合物在三个位点上含有多样性元素。该化合物的生物活性鉴定结果显示，它们对木瓜蛋白酶家族的半胱氨酸蛋白酶相较于丝氨酸、金属蛋白酶以及某些类别的半胱氨酸蛋白酶（如胱天蛋白酶）表现出显著的选择性。我们鉴定出了几个高效的组织蛋白酶L和S抑制剂。通过对接研究，我们利用SAR数据来理解实现组织蛋白酶S抑制所需的结构要素。这项研究为设计高度有效且选择性的木瓜蛋白酶家族半胱氨酸蛋白酶抑制剂奠定了基础。
• Identification and synthesis of a unique thiocarbazate cathepsin L inhibitor
  作者：Michael C. Myers、Parag P. Shah、Scott L. Diamond、Donna M. Huryn、Amos B. Smith

  DOI：10.1016/j.bmcl.2007.10.107

  日期：2008.1

  Library samples containing 2,5-disubstituted oxadiazoles were identified as potent hits in a high throughput screen (HTS) of the NIH Molecular Libraries Small Molecule Repository (MLSMR) directed at discovering inhibitors of cathepsin L. However, when synthesized in pure form, the putative actives were found to be devoid of biological activity. Analyses by LC-MS of original library samples indicated the presence of a number of impurities, in addition to the oxadiazoles. Synthesis and bioassay of the probable impurities led to the identification of a thiocarbazate that likely originated via ring opening of the oxadiazole. Previously unknown, thiocarbazates (-)-11 and (-)-12 were independently synthesized as single enantiomers and found to inhibit cathepsin L in the low nanomolar range. (C) 2007 Elsevier Ltd. All rights reserved.
• Design, synthesis, and evaluation of inhibitors of cathepsin L: Exploiting a unique thiocarbazate chemotype
  作者：Michael C. Myers、Parag P. Shah、Mary Pat Beavers、Andrew D. Napper、Scott L. Diamond、Amos B. Smith、Donna M. Huryn

  DOI：10.1016/j.bmcl.2008.04.065

  日期：2008.6

  Recently, we identified a thiocarbazate that exhibits potent inhibitory activity against human cathepsin L. Since this structure represents a novel chemotype with potential for activity against the entire cysteine protease family, we designed, synthesized, and assayed a series of analogs to probe the mechanism of action, as well as the structural requirements for cathepsin L activity. Molecular docking studies using coordinates of a papain-inhibitor complex as a model for cathepsin L provided useful insights. (C) 2008 Elsevier Ltd. All rights reserved.