(2S,3S)-2-{[2-[[2-(1S,2S)-[(1-carboxy-2-methylbutyl)carbamoyl]phenyl]dithio]benzoyl]amino}-3-methylpentanoic acid | 182149-25-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (2S,3S)-2-{[2-[[2-(1S,2S)-[(1-carboxy-2-methylbutyl)carbamoyl]phenyl]dithio]benzoyl]amino}-3-methylpentanoic acid
• 英文别名: (2S,3S)-2-[[2-[[2-[[(1S,2S)-1-carboxy-2-methyl-butyl]carbamoyl]phenyl]disulfanyl]benzoyl]amino]-3-methyl-pentanoic acid；(2S,3S)-2-[[2-[[2-[[(1S,2S)-1-carboxy-2-methylbutyl]carbamoyl]phenyl]disulfanyl]benzoyl]amino]-3-methylpentanoic acid
• CAS: 182149-25-3
• 化学式: C₂₆H₃₂N₂O₆S₂
• 分子量: 532.682
• InChiKey: SUQDXZBTWJQATJ-QDGJQWLKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  36
• 可旋转键数：
  13
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  183
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (2S,3S)-2-{[2-[[2-(1S,2S)-[(1-carboxy-2-methylbutyl)carbamoyl]phenyl]dithio]benzoyl]amino}-3-methylpentanoic acid 在 溴 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以91%的产率得到(2S,3S)-3-甲基-2-(3-氧代-1,2-苯并噻唑-2(3H)-基)戊酸
  参考文献：
  名称：

  Biophysical Characterization of Zinc Ejection from HIV Nucleocapsid Protein by Anti-HIV 2,2‘-Dithiobis[benzamides] and Benzisothiazolones

  摘要：

  HIV nucleocapsid protein (NCp7) has been suggested as a possible target for 2,2'-dithiobis[benzamide] and benzisothiazolone agents that inhibit viral replication in infected cells (Rice et al. Science 1995, 270, 1194-1197). The solution behavior of these compounds and the mechanistic events leading to removal of Zn from HIV nucleocapsid protein in vitro has been studied by electrospray ionization mass spectrometry, 500 MHz one- and two-dimensional nuclear magnetic resonance spectroscopy, and circular dichroism spectroscopy. We demonstrate that (1) Zn ejection is accompanied by formation of covalent complexes formed between the 2,2'-dithiobis[benzamide] monomers and Cys residues of Zn-depleted NCp7, (2) the rate of Zn ejection is faster for the C-terminal Zn finger and slower for the N-terminal finger, (3) Zn ejection results in a loss of structural integrity of the NCp7 protein, and (4) there is no appreciable interaction between a nonreactive iso stere of the lead 2,2'-dithiobis[benzamide] and NCp7 in buffered aqueous solution. These findings are discussed in terms of the mechanism of action of Zn ejection by aromatic 2,2'-dithiobis[benzamides].

  DOI：

  10.1021/jm960253w
• 作为产物：
  描述：

  tert-butyl (2S,3S)-2-[[2-[[2-[[(1S,2S)-1-tert-butoxycarbonyl-2-methyl-butyl]carbamoyl]phenyl]disulfanyl]benzoyl]amino]-3-methyl-pentanoate 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以42%的产率得到(2S,3S)-2-{[2-[[2-(1S,2S)-[(1-carboxy-2-methylbutyl)carbamoyl]phenyl]dithio]benzoyl]amino}-3-methylpentanoic acid
  参考文献：
  名称：

  针对核衣壳蛋白NCp7的新型抗HIV-1药物：2,2'-二硫代双苯甲酰胺。

  摘要：

  作为美国国家癌症研究所药物筛选计划的一部分，已经鉴定出了一类新的对人类免疫缺陷病毒HIV-1有活性的抗逆转录病毒药，并提出了HIV-1核衣壳蛋白NCp7作为抗病毒作用的靶标。2,2'-二硫代双-[4'-（氨磺酰基）苯甲酰苯胺]（3x）和2,2'-二硫代双（5-乙酰氨基）苯甲酰胺（10）代表了原型铅结构。制备了各种2,2'-二硫代双苯甲酰胺，并测试了它们的抗HIV-1活性，细胞毒性以及从NCf7的锌指中挤出锌的能力。结构-活性关系表明，从NCp7挤出锌的能力存在于2,2'-二硫代双苯甲酰胺核心结构中。3,3'和4,4'异构体没有活性。虽然许多基于核心结构的类似物保留了锌的挤出活性，但只有在具有羧酸，羧酰胺或苯磺酰胺官能团的狭窄衍生物中才发现最佳的总体抗HIV-1活性。这些功能组与降低NCp7的抗病毒效力或活性相比，对于降低细胞毒性而言更为重要。所有具有抗病毒活性的化合物也从NCp7中挤出锌。

  DOI：

  10.1016/s0968-0896(96)00269-6

文献信息

• Development and Pilot-Scale Demonstration of a Process for Inhibitors of the HIV Nucleocapsid Protein, NCp7
  作者：Phillip J. Fiore、Timothy P. Puls、Jonathan C. Walker

  DOI：10.1021/op9701191

  日期：1998.5.1

  A manufacturing-process to prepare two antiretroviral agents that denature the HIV-1 nucleocapsid protein (NCp7) has been developed and demonstrated on a pilot scale. 2,2'-Dithiobis-(benzoyl chloride) (4), prepared from commercially available 2,2'-dithiobis(benzoic acid) (3), was coupled directly with L-isoleucine to give the potential anti-HIV compound [S-(R*,R*)]- 2-[2-[[2-[(1-carboxy-2-methylbutyl)carbamoyl]phenyl]dithio]benzoyl]amino}-3-methylpentanoic acid (2) thereby eliminating the alpha-amino acid protection and deprotection steps used in the original synthesis. Compound 2 was oxidized by bromine to a second potential anti-HIV compound [S-(R*,R*)]-3-methyl-2-(3-oxo-3H-benzo[d]isothiazol-2-yl) pentanoic acid (1). The intermediacy of the hydrobromide salt of 1 provided an effective purity control in the production of the pharmaceutical agent. Cost, operational, safety, environmental, and equipment considerations were taken into account during the course of development.
• Org. Process Res. Deve. 1998, 2, 151-156
  作者：

  DOI：——

  日期：——
• A new class of anti-HIV-1 agents targeted toward the nucleocapsid protein NCp7: The 2,2′-dithiobisbenzamides
  作者：John M. Domagala、John P. Bader、Rocco D. Gogliotti、Joseph P. Sanchez、Michael A. Stier、Yuntao Song、J.V.N. Vara Prasad、Peter J. Tummino、Jeffrey Scholten、Patricia Harvey、Tod Holler、Steve Gracheck、Donald Hupe、William G. Rice、Robert Schultz

  DOI：10.1016/s0968-0896(96)00269-6

  日期：1997.3

  for anti-HIV-1 activity, cytotoxicity, and their ability to extrude zinc from the zinc fingers for NCp7. The structure-activity relationships demonstrated that the ability to extrude zinc from NCp7 resided in the 2,2'-dithiobisbenzamide core structure. The 3,3' and the 4,4' isomers were inactive. While many analogs based upon the core structure retained the zinc extrusion activity, the best overall

  作为美国国家癌症研究所药物筛选计划的一部分，已经鉴定出了一类新的对人类免疫缺陷病毒HIV-1有活性的抗逆转录病毒药，并提出了HIV-1核衣壳蛋白NCp7作为抗病毒作用的靶标。2,2'-二硫代双-[4'-（氨磺酰基）苯甲酰苯胺]（3x）和2,2'-二硫代双（5-乙酰氨基）苯甲酰胺（10）代表了原型铅结构。制备了各种2,2'-二硫代双苯甲酰胺，并测试了它们的抗HIV-1活性，细胞毒性以及从NCf7的锌指中挤出锌的能力。结构-活性关系表明，从NCp7挤出锌的能力存在于2,2'-二硫代双苯甲酰胺核心结构中。3,3'和4,4'异构体没有活性。虽然许多基于核心结构的类似物保留了锌的挤出活性，但只有在具有羧酸，羧酰胺或苯磺酰胺官能团的狭窄衍生物中才发现最佳的总体抗HIV-1活性。这些功能组与降低NCp7的抗病毒效力或活性相比，对于降低细胞毒性而言更为重要。所有具有抗病毒活性的化合物也从NCp7中挤出锌。
• Biophysical Characterization of Zinc Ejection from HIV Nucleocapsid Protein by Anti-HIV 2,2‘-Dithiobis[benzamides] and Benzisothiazolones
  作者：Joseph A. Loo、Tod P. Holler、Joseph Sanchez、Rocco Gogliotti、Lisa Maloney、Michael D. Reily

  DOI：10.1021/jm960253w

  日期：1996.1.1

  HIV nucleocapsid protein (NCp7) has been suggested as a possible target for 2,2'-dithiobis[benzamide] and benzisothiazolone agents that inhibit viral replication in infected cells (Rice et al. Science 1995, 270, 1194-1197). The solution behavior of these compounds and the mechanistic events leading to removal of Zn from HIV nucleocapsid protein in vitro has been studied by electrospray ionization mass spectrometry, 500 MHz one- and two-dimensional nuclear magnetic resonance spectroscopy, and circular dichroism spectroscopy. We demonstrate that (1) Zn ejection is accompanied by formation of covalent complexes formed between the 2,2'-dithiobis[benzamide] monomers and Cys residues of Zn-depleted NCp7, (2) the rate of Zn ejection is faster for the C-terminal Zn finger and slower for the N-terminal finger, (3) Zn ejection results in a loss of structural integrity of the NCp7 protein, and (4) there is no appreciable interaction between a nonreactive iso stere of the lead 2,2'-dithiobis[benzamide] and NCp7 in buffered aqueous solution. These findings are discussed in terms of the mechanism of action of Zn ejection by aromatic 2,2'-dithiobis[benzamides].