4,4-bis[8',8"-dichloro-2',2',2",2"-tetramethyl-4',4"-dioxo-6',6"-(1,3-benzodioxyl)]-3-buten-1-ol | 173173-59-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并二恶烷
• 英文名称: 4,4-bis[8',8"-dichloro-2',2',2",2"-tetramethyl-4',4"-dioxo-6',6"-(1,3-benzodioxyl)]-3-buten-1-ol
• 英文别名: 8-Chloro-6-[1-(8-chloro-2,2-dimethyl-4-oxo-1,3-benzodioxin-6-yl)-4-hydroxy-but-1-enyl]-2,2-dimethyl-1,3-benzodioxin-4-one；8-chloro-6-[1-(8-chloro-2,2-dimethyl-4-oxo-1,3-benzodioxin-6-yl)-4-hydroxybut-1-enyl]-2,2-dimethyl-1,3-benzodioxin-4-one
• CAS: 173173-59-6
• 化学式: C₂₄H₂₂Cl₂O₇
• 分子量: 493.34
• InChiKey: HRXHLPPEUPOTST-UHFFFAOYSA-N

物化性质

• 沸点：
  711.7±60.0 °C(Predicted)
• 密度：
  1.361±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  33
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  91.3
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4,4-bis[8',8"-dichloro-2',2',2",2"-tetramethyl-4',4"-dioxo-6',6"-(1,3-benzodioxyl)]-3-buten-1-ol 在 四溴化碳 、 三苯基膦 作用下， 以 乙腈 为溶剂， 反应 20.0h， 以56%的产率得到1-bromo-4,4-bis[8',8''-dichloro-2',2',2'',2''-tetramethyl-4',4''-dioxo-6',6''-(1,3-benzodioxyl)]-3-butene
  参考文献：
  名称：

  New Alkenyldiarylmethanes with Enhanced Potencies as Anti-HIV Agents Which Act as Non-Nucleoside Reverse Transcriptase Inhibitors

  摘要：

  Twenty-two new alkenyldiarylmethanes (ADAMs) were synthesized and evaluated for inhibition of HIV-1 replication. The most potent compound proved to be methyl 3',3 "-dichloro-4',4 "-dimethoxy-5', 5 "-bis(methoxycarbonyl)-6, (ADAM II), which displayed an EC50 of 13 nM for inhibition of the cytopathic effect of HIV-1(RF) in CEM-SS cells. ADAM II inhibited HIV-1 reverse transcriptase with an IC50 of 0.3 mu M but was inactive as an inhibitor of HIV-1 attachment/fusion to cells, protease, integrase, and the nucleocapsid protein. Molecular target-based and cell-based assays revealed that ADAM II acted biologically as a nonnucleoside reverse transcriptase inhibitor (NNRTI). ADAM II inhibited replication of a wide variety of laboratory, clinical, and clade-representative isolates of HIV-1 in T cell lines and cultures of peripheral blood mononuclear cells or monocyte/macrophages. Mutations that conferred resistance to ADAM II clustered at residues 101, 103, 108, 139, 179, 181, and 188, which line the nonnucleoside binding pocket of HIV-1 reverse transcriptase. However, HIV-1 NL4-3 strain expressing a mutation at residue 100 of reverse transcriptase, and an AZT-resistant virus, displayed increased sensitivity to ADAM II. Thus, ADAM II could serve as an adjunct therapy to AZT and NNRTIs that select for L100I resistance mutations.

  DOI：

  10.1021/jm9800595
• 作为产物：
  描述：

  8,8'-dichloro-2,2,2',2'-tetramethyl-4,4'-dioxo-6,6'-di(1,3-benzodioxyl) ketone 在 四丁基氟化铵 、 sodium hexamethyldisilazane 作用下， 以 四氢呋喃 为溶剂， 反应 25.5h， 生成 4,4-bis[8',8"-dichloro-2',2',2",2"-tetramethyl-4',4"-dioxo-6',6"-(1,3-benzodioxyl)]-3-buten-1-ol
  参考文献：
  名称：

  Correlation of Anti-HIV Potency with Lipophilicity in a Series of Cosalane Analogs Having Normal Alkenyl and Phosphodiester Chains as Cholestane Replacements

  摘要：

  In order to define the role of the cholestane moiety in the anti-HIV agent cosalane, a series of cosalane analogs was synthesized in which the cholestane ring system was replaced by normal alkenyl and phosphodiester substituents having varied chain lengths and lipophilicities. The compounds containing simple alkenyl substituents were found to be more potent as inhibitors of the cytopathic effect of HIV-1 in cell culture than the phosphodiesters. In addition, the potencies of the alkene congeners correlated positively with chain length and lipophilicity of the alkene. The results indicate that the cholestane moiety of cosalane functions as a lipophilic accessory appendage to escort the dichlorodisalicylmethane pharmacophore to a lipid environment.

  DOI：

  10.1021/jm950666h

文献信息

• Exploration of the effects of linker chain modifications on anti-HIV activities in a series of cosalane analogues
  作者：W. Marek Golebiewski、Robert F. Keyes、Mark Cushman

  DOI：10.1016/0968-0896(96)00159-9

  日期：1996.10

  The effects of linker chain modifications were investigated in a series of cosalane analogues. The modifications investigated included: (1) shortening the three-carbon linker chain between the dichlorodisalicylmethane and the cholestane moiety by one carbon atom; (2) lengthening the linker chain by one carbon; (3) hydrogenation of the double bond in the linker chain; (4) changing the point of attachment of the linker chain from C-3 to C-6; (5) insertion of a phosphate between the steroid and the linker chain. With the exception of the phosphate modification, which abolished anti-HIV activity and increased cytotoxicity, the linker chain modifications produced relatively minor changes in anti-HIV activity and increased cytotoxicity, the linker chain modifications produced relatively minor changes in anti-HIV potency. The steroid and attached linker chain of cosalane therefore appear only to provide a general lipophilic appendage for the dichlorodisalicylmethane pharmacophore.
• Correlation of Anti-HIV Potency with Lipophilicity in a Series of Cosalane Analogs Having Normal Alkenyl and Phosphodiester Chains as Cholestane Replacements
  作者：Robert F. Keyes、W. Marek Golebiewski、Mark Cushman

  DOI：10.1021/jm950666h

  日期：1996.1.1

  In order to define the role of the cholestane moiety in the anti-HIV agent cosalane, a series of cosalane analogs was synthesized in which the cholestane ring system was replaced by normal alkenyl and phosphodiester substituents having varied chain lengths and lipophilicities. The compounds containing simple alkenyl substituents were found to be more potent as inhibitors of the cytopathic effect of HIV-1 in cell culture than the phosphodiesters. In addition, the potencies of the alkene congeners correlated positively with chain length and lipophilicity of the alkene. The results indicate that the cholestane moiety of cosalane functions as a lipophilic accessory appendage to escort the dichlorodisalicylmethane pharmacophore to a lipid environment.
• New Alkenyldiarylmethanes with Enhanced Potencies as Anti-HIV Agents Which Act as Non-Nucleoside Reverse Transcriptase Inhibitors
  作者：Mark Cushman、Agustin Casimiro-Garcia、Elzbieta Hejchman、Jeffrey A. Ruell、Mingjun Huang、Catherine A. Schaeffer、Karen Williamson、William G. Rice、Robert W. Buckheit

  DOI：10.1021/jm9800595

  日期：1998.6.1

  Twenty-two new alkenyldiarylmethanes (ADAMs) were synthesized and evaluated for inhibition of HIV-1 replication. The most potent compound proved to be methyl 3',3 "-dichloro-4',4 "-dimethoxy-5', 5 "-bis(methoxycarbonyl)-6, (ADAM II), which displayed an EC50 of 13 nM for inhibition of the cytopathic effect of HIV-1(RF) in CEM-SS cells. ADAM II inhibited HIV-1 reverse transcriptase with an IC50 of 0.3 mu M but was inactive as an inhibitor of HIV-1 attachment/fusion to cells, protease, integrase, and the nucleocapsid protein. Molecular target-based and cell-based assays revealed that ADAM II acted biologically as a nonnucleoside reverse transcriptase inhibitor (NNRTI). ADAM II inhibited replication of a wide variety of laboratory, clinical, and clade-representative isolates of HIV-1 in T cell lines and cultures of peripheral blood mononuclear cells or monocyte/macrophages. Mutations that conferred resistance to ADAM II clustered at residues 101, 103, 108, 139, 179, 181, and 188, which line the nonnucleoside binding pocket of HIV-1 reverse transcriptase. However, HIV-1 NL4-3 strain expressing a mutation at residue 100 of reverse transcriptase, and an AZT-resistant virus, displayed increased sensitivity to ADAM II. Thus, ADAM II could serve as an adjunct therapy to AZT and NNRTIs that select for L100I resistance mutations.