铵5-[(Z)-1-(3-羧基-5-氯-4-羟基苯基)-4-[(3S,10S,13R,17R)-10,13-二甲基-17-(6-甲基庚烷-2-基)-2,3,4,5,6,7,8,9,11,12,14,15,16,17-十四氢-1H-环戊二烯并[a]菲-3-基]丁-1-烯基]-3-氯-2-羟基苯甲酸酯 | 154212-56-3

• 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
• 中文名称: 铵5-[(Z)-1-(3-羧基-5-氯-4-羟基苯基)-4-[(3S,10S,13R,17R)-10,13-二甲基-17-(6-甲基庚烷-2-基)-2,3,4,5,6,7,8,9,11,12,14,15,16,17-十四氢-1H-环戊二烯并[a]菲-3-基]丁-1-烯基]-3-氯-2-羟基苯甲酸酯
• 英文名称: cosalane
• 英文别名: 5-[1-(3-carboxy-5-chloro-4-hydroxyphenyl)-4-[(3S,5S,8R,9S,10S,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl]but-1-enyl]-3-chloro-2-hydroxybenzoic acid
• CAS: 154212-56-3
• 化学式: C₄₅H₆₀Cl₂O₆
• 分子量: 767.874
• InChiKey: VOJOOGPALCATLT-ZFQBPCNVSA-N

物化性质

• 沸点：
  797.4±60.0 °C(Predicted)
• 密度：
  1.191±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  16.5
• 重原子数：
  53
• 可旋转键数：
  12
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  115
• 氢给体数：
  4
• 氢受体数：
  6

制备方法与用途

Cosalane (NSC 658586) 是一种有效的 HIV 复制抑制剂。在体外实验中，它能够阻断 CCR7 与其天然配体 CCL19 和 CCL21 的结合。在人类中，其对 CCL19/CCL21 的 IC50 值分别为 0.207 μM 和 2.66 μM；而在小鼠中，这些值分别为 0.193 μM 和 1.98 μM。

反应信息

• 作为反应物：
  描述：

  铵5-[(Z)-1-(3-羧基-5-氯-4-羟基苯基)-4-[(3S,10S,13R,17R)-10,13-二甲基-17-(6-甲基庚烷-2-基)-2,3,4,5,6,7,8,9,11,12,14,15,16,17-十四氢-1H-环戊二烯并[a]菲-3-基]丁-1-烯基]-3-氯-2-羟基苯甲酸酯 在 sodium hydroxide 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 36.0h， 生成 5'',5'''-di[(2-carboxyethyl)carbamoyl]-3'',3'''-dichloro-4'',4'''-dihydroxy-4',4'-diphenyl-3β-(3'-buten-1'-yl)cholestane
  参考文献：
  名称：

  Correlation of Anti-HIV Activity with Anion Spacing in a Series of Cosalane Analogues with Extended Polycarboxylate Pharmacophores

  摘要：

  Cosalane and its synthetic derivatives inhibit the binding of gp120 to CD4 as well as the fusion of the viral envelope with the cell membrane. The binding of the cosalanes to CD4 is proposed to involve ionic interactions of the negatively charged carboxylates of the ligands with positively charged arginine and lysine amino acid side chains of the protein. To investigate the effect of anion spacing on anti-HIV activity in the cosalane system, a series of cosalane tetracarboxylates was synthesized in which the two proximal and two distal carboxylates are separated by 6-12 atoms. Maximum activity was observed when the proximal and distal carboxylates are separated by 8 atoms. In a series of cosalane amino acid derivatives containing glutamic acid, glycine, aspartic acid, beta -alanine, leucine, and phenylalanine residues, maximum activity was displayed by the di(glutamic acid) analogue. A hypothetical model has been devised for the binding of the cosalane di(glutamic acid) conjugate to CD4. In general, the compounds in this series are more potent against HIV-1(RF) in CEM-SS cells than they are vs HIV-1(IIIB) in MT-4 cells, and they are least potent vs HIV-2(ROD) in MT-4 cells.

  DOI：

  10.1021/jm000290u
• 作为产物：
  描述：

  5-Alpha-胆甾烷-3-酮 在 platinum(IV) oxide 正丁基锂 、 四丁基氟化铵 、 氢气 作用下， 反应 28.33h， 生成 铵5-[(Z)-1-(3-羧基-5-氯-4-羟基苯基)-4-[(3S,10S,13R,17R)-10,13-二甲基-17-(6-甲基庚烷-2-基)-2,3,4,5,6,7,8,9,11,12,14,15,16,17-十四氢-1H-环戊二烯并[a]菲-3-基]丁-1-烯基]-3-氯-2-羟基苯甲酸酯
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Cosalane, a Novel Anti-HIV Agent Which Inhibits Multiple Features of Virus Reproduction

  摘要：

  Cosalane (3), a novel anti-HIV agent having a disalicylmethane unit linked to C-3 of cholestane by a three-carbon Linker, was synthesized from commercially available starting materials by a convergent route. Cosalane proved to be a potent inhibitor of HIV with a broad range of activity against a variety of laboratory, drug-resistant, and clinical HIV-1 isolates, HIV-2, and Rauscher murine leukemia virus. The cytotoxicity of cosalane is relatively low as reflected by an in vitro therapeutic index of > 100. Although cosalane inhibits HIV-1 reverse transcriptase and protease, time of addition experiments indicate that it prevents the cytopathic effect of HIV by acting earlier than reverse transcription in the viral replication cycle. The available evidence indicates that the primary mechanism of action of cosalane involves inhibition of gp120-CD4 binding as well as inhibition of a postattachment event prior to reverse transcription.

  DOI：

  10.1021/jm00045a008

文献信息

• Synthesis of a cosalane analog with an extended polyanionic pharmacophore conferring enhanced potency as an anti-HIV agent
  作者：Mark Cushman、Shabana Insaf、Jeffrey A. Ruell、Catherine A. Schaeffer、William G. Rice

  DOI：10.1016/s0960-894x(98)00121-8

  日期：1998.4

  A novel cosalane analog having an extended polyanionic pharmacophore was synthesized in order to target specific cationic residues on the surface of CD4. The design rationale is based on a hypothetical binding model of cosalane to the surface of the protein. The new analog displayed an EC50 of 0.55 mu M as an inhibitor of the cytopathic effect of HIV-1(RF) in CEM-SS cells, which represents a significant increase in potency over cosalane itself (EC50 5.1 mu M) Both cosalane and the new analog are inhibitors of viral entry into target cells. (C) 1998 Elsevier Science Ltd. All rights reserved.
• Extension of the Polyanionic Cosalane Pharmacophore as a Strategy for Increasing Anti-HIV Potency
  作者：Mark Cushman、Shabana Insaf、Gitendra Paul、Jeffrey A. Ruell、Erik De Clercq、Dominique Schols、Christophe Pannecouque、Myriam Witvrouw、Catherine A. Schaeffer、Jim A. Turpin、Karen Williamson、William G. Rice

  DOI：10.1021/jm980727m

  日期：1999.5.1

  The anti-HIV agent cosalane inhibits both the binding of gp120 to CD4 as well as an undefined postattachment event prior to reverse transcription. Several cosalane analogues having an extended polyanionic "pharmacophore" were designed based on a hypothetical model of the binding of cosalane to CD4. The analogues were synthesized, and a number of them displayed anti-HIV activity. One of the new analogues was found to possess enhanced potency as an anti-HIV agent relative to cosalane itself. Although the new analogues inhibited both HIV-1 and HTV-2, they were more potent as inhibitors of HIV-1 than HIV-2. Mechanism of action studies indicated that the most potent of the new analogues inhibited fusion of the viral envelope with the cell membrane at lower concentrations than it inhibited attachment, suggesting inhibition of fusion as the primary mechanism of action.
• Design, Synthesis, and Biological Evaluation of Cosalane, a Novel Anti-HIV Agent Which Inhibits Multiple Features of Virus Reproduction
  作者：Mark Cushman、W. Marek Golebiewski、James B. McMahon、Robert W. Buckheit、David J. Clanton、Owen Weislow、Rudiger D. Haugwitz、John P. Bader、Lisa Graham、William G. Rice

  DOI：10.1021/jm00045a008

  日期：1994.9

  Cosalane (3), a novel anti-HIV agent having a disalicylmethane unit linked to C-3 of cholestane by a three-carbon Linker, was synthesized from commercially available starting materials by a convergent route. Cosalane proved to be a potent inhibitor of HIV with a broad range of activity against a variety of laboratory, drug-resistant, and clinical HIV-1 isolates, HIV-2, and Rauscher murine leukemia virus. The cytotoxicity of cosalane is relatively low as reflected by an in vitro therapeutic index of > 100. Although cosalane inhibits HIV-1 reverse transcriptase and protease, time of addition experiments indicate that it prevents the cytopathic effect of HIV by acting earlier than reverse transcription in the viral replication cycle. The available evidence indicates that the primary mechanism of action of cosalane involves inhibition of gp120-CD4 binding as well as inhibition of a postattachment event prior to reverse transcription.
• Correlation of Anti-HIV Activity with Anion Spacing in a Series of Cosalane Analogues with Extended Polycarboxylate Pharmacophores
  作者：Kalpathy C. Santhosh、Gitendra C. Paul、Erik De Clercq、Christophe Pannecouque、Myriam Witvrouw、Tracy L. Loftus、Jim A. Turpin、Robert W. Buckheit,、Mark Cushman

  DOI：10.1021/jm000290u

  日期：2001.3.1

  Cosalane and its synthetic derivatives inhibit the binding of gp120 to CD4 as well as the fusion of the viral envelope with the cell membrane. The binding of the cosalanes to CD4 is proposed to involve ionic interactions of the negatively charged carboxylates of the ligands with positively charged arginine and lysine amino acid side chains of the protein. To investigate the effect of anion spacing on anti-HIV activity in the cosalane system, a series of cosalane tetracarboxylates was synthesized in which the two proximal and two distal carboxylates are separated by 6-12 atoms. Maximum activity was observed when the proximal and distal carboxylates are separated by 8 atoms. In a series of cosalane amino acid derivatives containing glutamic acid, glycine, aspartic acid, beta -alanine, leucine, and phenylalanine residues, maximum activity was displayed by the di(glutamic acid) analogue. A hypothetical model has been devised for the binding of the cosalane di(glutamic acid) conjugate to CD4. In general, the compounds in this series are more potent against HIV-1(RF) in CEM-SS cells than they are vs HIV-1(IIIB) in MT-4 cells, and they are least potent vs HIV-2(ROD) in MT-4 cells.