3',3''-dichloro-4',4''-dimethoxy-5',5''-bis(methoxycarbonyl)-3,3-diphenylpropenoic acid | 207743-06-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3',3''-dichloro-4',4''-dimethoxy-5',5''-bis(methoxycarbonyl)-3,3-diphenylpropenoic acid
• 英文别名: 3,3-Bis[3-chloro-4-methoxy-5-(methoxycarbonyl)phenyl]prop-2-enoic acid；3,3-bis(3-chloro-4-methoxy-5-methoxycarbonylphenyl)prop-2-enoic acid
• CAS: 207743-06-4
• 化学式: C₂₁H₁₈Cl₂O₈
• 分子量: 469.275
• InChiKey: PQWYYHXNTVLOPG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  31
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  108
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  3',3''-dichloro-4',4''-dimethoxy-5',5''-bis(methoxycarbonyl)-3,3-diphenylpropenoic acid 在 sodium hydroxide 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 60.0h， 生成 N-(5α-cholestan-3β-yl)-N-[6,6-bis(3'-carboxy-5'-chloro-4'-methoxyphenyl)-5-hexenyl]-3,3-bis(3'-carboxy-5'-chloro-4'-methoxyphenyl)-2-propenamide
  参考文献：
  名称：

  Synthesis and anti-HIV activity of cosalane analogues incorporating two dichlorodisalicylmethane pharmacophore fragments

  摘要：

  A new series of cosalane analogues incorporating two fragments of the dichlorodisalicylmethane pharmacophore has been synthesized. In order to identify the position for the attachment of the pharmacophore fragments to the steroid ring that results in the most potent analogues, two types of compounds were designed. In the first type, the two pharmacophore fragments were attached at C-3 and C-17 of the steroid ring by using appropriate linker units. In the second type, both pharmacophore groups were connected to C-3 of the steroid through an alkenyl chain containing an amide moiety. All of the new compounds displayed antiviral activity versus HIV-1(RF), HIV-1(IIIB), and HIV-2(ROD) in cell culture. The relative potencies of the compounds resulting from the two attachment strategies were found to depend on the viral strain as well as the cell type, Overall, the attachment of the second pharmacophore did not result in either a large gain or a large loss in anti-HIV activity, and the results are therefore consistent with the hypothesis that the two pharmacophores act independently, and one at a time, with positively charged amino acid side chains present on the surface of gp120 and CD4. (C) 2001 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(01)00152-3
• 作为产物：
  描述：

  2-(trimethylsilyl)ethyl 3',3''-dichloro-4',4''-dimethoxy-5',5''-bis(methoxycarbonyl)-3,3-diphenylpropenoate 在 四丁基氟化铵 作用下， 以 四氢呋喃 为溶剂， 反应 1.5h， 以83%的产率得到3',3''-dichloro-4',4''-dimethoxy-5',5''-bis(methoxycarbonyl)-3,3-diphenylpropenoic acid
  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

文献信息

• Synthesis and anti-HIV activity of cosalane analogues incorporating nitrogen in the linker chain
  作者：Agustin Casimiro-Garcia、Erik De Clercq、Christophe Pannecouque、Myriam Witvrouw、Tracy L. Stup、Jim A. Turpin、Robert W. Buckheit、Mark Cushman

  DOI：10.1016/s0968-0896(99)00269-2

  日期：2000.1

  Introduction of an amido group or an amino moiety into the alkenyl linker chain of cosalane (1) provided a new series of analogues 3-8. The new compounds were evaluated as inhibitors of the cytopathic effect of HIV-1 and HIV-2 in cell culture. The replacement of the 1' and 2' carbons in the linker chain of I by an amido group was generally tolerated. The length of the linker chain and the stereochemistry

  将氨基或氨基部分引入到al草烷（1）的烯基连接链中提供了一系列新的类似物3-8。新化合物被评估为在细胞培养物中抑制HIV-1和HIV-2的细胞病变作用。通常容许I的连接链中的1'和2'碳被酰胺基取代。连接链的长度和甾族环C-3处取代基的立体化学对抗病毒活性和效价都有重要影响。将氨基部分结合到接头中完全消除了抗HIV活性。在HIV复制周期中有几个步骤被提议作为治疗剂开发的目标（De Clercq，EJ Med。Chem。1995，38，2491; De Clercq，E.Pure Appl.Chem。1998，70， 567）。然而，当前批准的抗HIV药物仅针对病毒酶逆转录酶或蛋白酶（Carpenter。CCJ; MA菲斯切尔; SM汉默; Hirsch女士; DM雅各布森; DA; Katzenstein; JSG Montaner; DD里奇曼;密苏里州萨格（Saag）;密歇根州Scho
• Synthesis and anti-HIV activity of cosalane analogues incorporating two dichlorodisalicylmethane pharmacophore fragments
  作者：Agustin Casimiro-Garcia、Erik De Clercq、Christophe Pannecouque、Myriam Witvrouw、Tracy L Loftus、Jim A Turpin、Robert W Buckheit、Phillip E Fanwick、Mark Cushman

  DOI：10.1016/s0968-0896(01)00152-3

  日期：2001.11

  A new series of cosalane analogues incorporating two fragments of the dichlorodisalicylmethane pharmacophore has been synthesized. In order to identify the position for the attachment of the pharmacophore fragments to the steroid ring that results in the most potent analogues, two types of compounds were designed. In the first type, the two pharmacophore fragments were attached at C-3 and C-17 of the steroid ring by using appropriate linker units. In the second type, both pharmacophore groups were connected to C-3 of the steroid through an alkenyl chain containing an amide moiety. All of the new compounds displayed antiviral activity versus HIV-1(RF), HIV-1(IIIB), and HIV-2(ROD) in cell culture. The relative potencies of the compounds resulting from the two attachment strategies were found to depend on the viral strain as well as the cell type, Overall, the attachment of the second pharmacophore did not result in either a large gain or a large loss in anti-HIV activity, and the results are therefore consistent with the hypothesis that the two pharmacophores act independently, and one at a time, with positively charged amino acid side chains present on the surface of gp120 and CD4. (C) 2001 Elsevier Science Ltd. All rights reserved.
• 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.