Methyl 3-bromo-5-[1-(3-bromo-4-methoxy-5-methoxycarbonyl-phenyl)-6-methoxy-6-oxo-hex-1-enyl]-2-methoxy-benzoate

• 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-bromo-5-[1-(3-bromo-4-methoxy-5-methoxycarbonyl-phenyl)-6-methoxy-6-oxo-hex-1-enyl]-2-methoxy-benzoate
• 英文别名: methyl 3-bromo-5-[1-(3-bromo-4-methoxy-5-methoxycarbonylphenyl)-6-methoxy-6-oxohex-1-enyl]-2-methoxybenzoate
• 化学式: C₂₅H₂₆Br₂O₈
• 分子量: 614.285
• InChiKey: UMQKWZFOHPXVRL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 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：

  氰化亚铜 、 Methyl 3-bromo-5-[1-(3-bromo-4-methoxy-5-methoxycarbonyl-phenyl)-6-methoxy-6-oxo-hex-1-enyl]-2-methoxy-benzoate 以 N,N-二甲基甲酰胺 为溶剂， 反应 22.0h， 以19%的产率得到Dimethyl 3,3'-(6-methoxy-6-oxohex-1-ene-1,1-diyl)bis(5-cyano-6-methoxybenzoate)
  参考文献：
  名称：

  Design, Synthesis, Anti-HIV Activities, and Metabolic Stabilities of Alkenyldiarylmethane (ADAM) Non-nucleoside Reverse Transcriptase Inhibitors

  摘要：

  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.

  DOI：

  10.1021/jm049916x
• 作为产物：
  描述：

  5-氧代戊酸甲酯 、 [3',3''-dibromo-4',4''-dimethoxy-5',5''-di(methoxycarbonyl)diphenyl]methanone 在 tetrachlorobis(tetrahydrofuran)titanium(IV) 、 锌 作用下， 以 四氢呋喃 为溶剂， 反应 1.5h， 以22.8%的产率得到Methyl 3-bromo-5-[1-(3-bromo-4-methoxy-5-methoxycarbonyl-phenyl)-6-methoxy-6-oxo-hex-1-enyl]-2-methoxy-benzoate
  参考文献：
  名称：

  Novel Modifications in the Alkenyldiarylmethane (ADAM) Series of Non-Nucleoside Reverse Transcriptase Inhibitors

  摘要：

  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.

  DOI：

  10.1021/jm990343b

文献信息

• Alkenyldiarylmethanes, Fused Analogs And Syntheses Thereof
  申请人：Cushman Mark S.

  公开号：US20080300288A1

  公开（公告）日：2008-12-04

  Non-nucleoside inhibitors of HIV-1 reverse transcriptase are described. Such inhibitors may 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 Non-nucleoside inhibitors of HIV-1 reverse transcriptase.

  HIV-1反转录酶的非核苷类抑制剂被描述。这些抑制剂可以作为治疗HIV感染的联合疗法的一部分使用。本文描述的化合物具有抗病毒效力。此外，本文描述的化合物具有代谢稳定性。本文还描述了制备HIV-1反转录酶非核苷类抑制剂的过程。
• Investigation of the alkenyldiarylmethane non-nucleoside reverse transcriptase inhibitors as potential cAMP phosphodiesterase-4B2 inhibitors
  作者：Matthew D. Cullen、York-Fong Cheung、Miles D. Houslay、Tracy L. Hartman、Karen M. Watson、Robert W. Buckheit、Christophe Pannecouque、Erik De Clercq、Mark Cushman

  DOI：10.1016/j.bmcl.2007.12.015

  日期：2008.2

  The alkenyldiarylmethanes ( ADAMs) are currently being investigated as non- nucleoside HIV- 1 reverse transcriptase inhibitors ( NNRTIs) of potential value in the treatment of HIV infection and AIDS. During the course of these studies, a number of ADAM analogues have been identified that protect HIV- infected cells from the cytopathic effects of the virus by an unknown, HIV- 1 RT- independent mechanism. Since the phosphodiesterase 4 family is required for HIV infection, the effect of various ADAMs on the activity of PDE4B2 was investigated in an effort to determine if the ADAMs could possibly be targeting phosphodiesterases. Six compounds representative of the ADAM class were tested for inhibition of cAMP hydrolysis by PDE4B2 enzymatic activity. Four ADAMs were found to be weak inhibitors of PDE4B2 and two of them were inactive. The experimental results are consistent with an antiviral mechanism that does not include inhibition of PDE4 isoforms. (C) 2007 Elsevier Ltd. All rights reserved.
• 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.