methyl-3',3-dichloro-4',4-dimethoxy-5',5-bis(methoxycarbonyl)-6,6-diphenylhexenoate | 204864-54-0

• 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: methyl-3',3-dichloro-4',4-dimethoxy-5',5-bis(methoxycarbonyl)-6,6-diphenylhexenoate
• 英文别名: Adam II；methyl 3-chloro-5-[1-(3-chloro-4-methoxy-5-methoxycarbonylphenyl)-6-methoxy-6-oxohex-1-enyl]-2-methoxybenzoate
• CAS: 204864-54-0
• 化学式: C₂₅H₂₆Cl₂O₈
• 分子量: 525.383
• InChiKey: LSBDJGANJWONSP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  35
• 可旋转键数：
  13
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  97.4
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  methyl-3',3-dichloro-4',4-dimethoxy-5',5-bis(methoxycarbonyl)-6,6-diphenylhexenoate 在 氢氧化钾 作用下， 以 甲醇 为溶剂， 反应 24.0h， 以91.7%的产率得到3',3''-dichloro-4',4''-dimethoxy-5',5''-bis(carboxy)-6,6-diphenyl-5-hexenoic 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
• 作为产物：
  描述：

  戊酸甲酯三苯基溴化膦 、 3,3'-dichloro-4,4'-dimethoxy-5,5'-bis(methoxycarbonyl)benzophenone 在 sodium hexamethyldisilazane 作用下， 生成 methyl-3',3-dichloro-4',4-dimethoxy-5',5-bis(methoxycarbonyl)-6,6-diphenylhexenoate
  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

• Design, Synthesis, Anti-HIV Activities, and Metabolic Stabilities of Alkenyldiarylmethane (ADAM) Non-nucleoside Reverse Transcriptase Inhibitors
  作者：Maximilian A. Silvestri、Muthukaman Nagarajan、Erik De Clercq、Christophe Pannecouque、Mark Cushman

  DOI：10.1021/jm049916x

  日期：2004.6.1

  The alkenyldiarylmethane (ADAM) HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) are effective anti-HIV agents in cell culture. However, the potential clinical utility of the ADAMs is expected to be limited by the presence of methyl ester moieties that are likely to be metabolized by nonspecific esterases in blood plasma to biologically inactive carboxylic acid derivatives. The present investigation was therefore undertaken to investigate the anti-HIV activities of the ADAMs versus HIV-1(IIIB) and HIV-2(ROD) in MT-4 cells and the stabilities of the biologically active ADAMs in rat plasma. The ADAMs displayed a wide range of metabolic stabilities in rat plasma, with half-lives ranging from 0.9 to 76.6 min. A wide assortment of structural modifications was tolerated, with 18 of the 32 compounds tested displaying EC50 values between 0.3 and 3.7 muM versus HIV-1(IIIB) in MT-4 cells, 3 compounds in the EC50 = 13.2-35.4 muM range, and the remaining compounds inactive. Consistent with the mechanism of action of the ADAMs as NNRTIs, they were inactive or displayed comparatively low activity versus HIV-2ROD. The replacement of the two aromatic methyl ester substituents in one of the most active ADAMs (EC50 = 0.6 muM) with two methyl thioester groups resulted in an increase in plasma half-life from 5.8 to 55.3 min, while maintaining the antiviral potency at the EC50 = 1.8 muM level. At the same time, the bis(thioester) modification was less cytotoxic to uninfected MT-4 cells, with a CC50 of >224 muM versus 160 muM for the parent compound.
• Novel Modifications in the Alkenyldiarylmethane (ADAM) Series of Non-Nucleoside Reverse Transcriptase Inhibitors
  作者：Agustin Casimiro-Garcia、Mark Micklatcher、Jim A. Turpin、Tracy L. Stup、Karen Watson、Robert W. Buckheit、Mark Cushman

  DOI：10.1021/jm990343b

  日期：1999.11.1

  In an effort to obtain more insight into the interaction between HIV-1 reverse transcriptase and the alkenyldiarylmethanes (ADAMs), a new series of compounds has been synthesized and evaluated for inhibition of HIV-1 replication. The modifications reported in this new series include primarily changes to the alkenyl chain. The most potent compound proved to be methyl 3', 3 "-dibromo-4',4 "-dimethoxy-5',5 "-bis(methoxycarbonyl)-6,6-diphenyl-5-hexanoate (28), which displayed an EC50 of 1.3 nM for inhibition of the cytopathic effect of HIV-1(RF) in CEM-SS cells. ADAM 28 inhibited HIV-1 reverse transcriptase with an IC50 of 0.3 mu M. Mutations that conferred greater than 10-fold resistance to ADAM 28 clustered at residues Val 106, Val 179, Tyr 181, and Tyr 188. Results derived from this series indicate that ADAMs containing chlorines in the aromatic rings might bind to HIV-1 reverse transcriptase in a slightly different mode when compared with those analogues incorporating bromine in the aromatic rings.
• Synthesis of a non-nucleoside reverse transcriptase inhibitor in the alkenyldiarylmethane (ADAM) series with optimized potency and therapeutic index
  作者：Mark Cushman、Agustin Casimiro-Garcia、Karen Williamson、William G. Rice

  DOI：10.1016/s0960-894x(97)10214-1

  日期：1998.1

  A novel alkenyldiarylmethane (ADAM) analog has been synthesized with enhanced potency as an anti-HIV agent. The new compound (ADAM II) inhibits the cytopathic effect of HIV-1(RF) in CEM-SS cells with an EC50 of 13 nM, while it shows cytotoxicity with a CC50 of 31.6 mu M, providing a therapeutic index of 2430. ADAM II is a non-nucleoside reverse transcriptase inhibitor, displaying an IC50 of 0.3 mu M with poly(rC) oligo(dG) as the template/primer. (C) 1998 Elsevier Science Ltd. All rights reserved.
• [EN] ALKENYLDIARYLMETHANES HAVING NITROGEN-CONTAINING CARBOXYLIC ACID DERIVATIVES<br/>[FR] ALCÉNYLDIARYLMÉTHANES PRÉSENTANT DES DÉRIVÉS D'ACIDE CARBOXYLIQUE CONTENANT DE L'AZOTE
  申请人：CUSHMAN MARK S

  公开号：WO2008119028A1

  公开（公告）日：2008-10-02

  [EN] Alkenydiarylmethane compounds are described. Such compounds are a class of non-nucleoside inhibitors of HIV-I reverse transcriptase, which may also be used as part of a combination therapy to treat HIV infection. Compounds described herein exhibit antiviral potency. In addition, compounds described herein exhibit metabolic stability. Also described herein are processes for preparing alkenydiarylmethane compounds.
  [FR] La présente invention concerne des composés alcényldiarylméthanes. Ces composés constituent une catégorie d'inhibiteurs non-nucléosides de la transcriptase inverse du VIH-I, qui peuvent également être utilisés dans le cadre d'une thérapie combinatoire visant à traiter une infection par le VIH. Les composés décrits ici présentent une activité antivirale. Ces composés possèdent en outre une stabilité métabolique. La présente invention concerne également des procédés de préparation de composés alcényldiarylméthanes.
• 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.