meso-2,3-bis(3,4-dihydroxybenzyl)succinic acid

• 分子结构分类: 有机化合物 - 木脂素、新木脂素和相关化合物 - 二苄基丁烷木脂素
• 英文名称: meso-2,3-bis(3,4-dihydroxybenzyl)succinic acid
• 英文别名: 2,3-Bis(3,4-dihydroxybenzyl)succinic acid；2,3-bis[(3,4-dihydroxyphenyl)methyl]butanedioic acid
• 化学式: C₁₈H₁₈O₈
• 分子量: 362.336
• InChiKey: HEWZPXBMFIXHJK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  26
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  156
• 氢给体数：
  6
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  3,4-二甲氧基苯丙酸 在 三溴化硼 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 meso-2,3-bis(3,4-dihydroxybenzyl)succinic acid
  参考文献：
  名称：

  Catechol-Substituted l -Chicoric acid analogues as HIV integrase inhibitors

  摘要：

  HIV integrase catalyzes the integration of HIV DNA copy into the host cell DNA, which is essential for the production of progeny viruses. L-Chicoric acid and dicaffeoylquinic acids, isolated from plants, are well known potent inhibitors of HIV integrase. The common structural features of these inhibitors are caffeic acid derivatives connected to tartaric acid or quinic acid through ester bonds. In the present study, we have synthesized and tested the inhibitory activities of a new type of HIV IN inhibitors, which has catechol groups in place of caffeoyl groups in the structure of L-chicoric acid. Upon substitution of catechol groups at succinic acid, pyrrol dicarboxylic acid, maleimide or maleic anhydride, the inhibitory activities (IC50 = 3.8-23.6 muM) were retained or remarkably increased when compared to parent compound L-chicoric acid (IC50 = 13.7 muM). (C) 2003 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2003.09.046

文献信息

• Novel HIV integrase inhibitors and HIV therapy based on drug combinations including integrase inhibitors
  申请人：Robinson W. Edward

  公开号：US20050049242A1

  公开（公告）日：2005-03-03

  The present invention includes a group of novel compounds that are demonstrated to potently and selectively inhibit HIV integrase (IN) activity in vitro and to potently inhibit HIV replication in live, cultured cells at non-toxic concentrations. The novel compounds disclosed include 2,3-di(3,4-dihydroxy-dihydroxydihydrocinnamoyl)-L-tartaric acid, 2,3-di-(3,4-dihydroxybenzoyl)-L-tartaric acid, 2,3-di-(3,4-dihydroxyphenylacetyl)-L-tartaric acid, 2,3-di-(3,4,5-trihydroxybenzoyl-L-tartaric acid, 2,3-dicaffeoyldiamidopropionic acid, 1,2,-dicaffeoyl-L-glyceric acid, bis,-3,4-dicaffeoyldiamidobenzoic acid, di-3,4-dihydroxybenzylidene succinic acid, di-3,4-dihydrodihydroxybenzylidine succinic acid, 2,3-dicaffeoyl-L-serine, bis-dicaffeoyl-L-isoserine and 1,4-dicaffeoyl-L-lysine. Tests of integrase inhibitors with 2′,3′-dideoxycytidine, zidovudine and nelfinavir (protease inhibitor) indicated a potent synergy against reverse transcriptase inhibitor resistant virus. The potential benefit from the addition of integrase inhibitors to combination drug therapies is significant.

  本发明包括一组新颖的化合物，已被证明能够在体外强力且选择性地抑制HIV整合酶（IN）活性，并在非毒性浓度下有效抑制活体培养细胞中的HIV复制。所披露的新颖化合物包括2,3-二（3,4-二羟基-二羟基二羟基肉桂酰）-L-酒石酸，2,3-二（3,4-二羟基苯甲酰）-L-酒石酸，2,3-二（3,4-二羟基苯乙酰）-L-酒石酸，2,3-二（3,4,5-三羟基苯甲酰）-L-酒石酸，2,3-二咖啡酰二氨基丙酸，1,2-二咖啡酰-L-甘油酸，双-3,4-二咖啡酰二氨基苯甲酸，二-3,4-二羟基苯乙烯琥珀酸，二-3,4-二羟基二羟基苯乙烯琥珀酸，2,3-二咖啡酰-L-丝氨酸，双咖啡酰-L-异丝氨酸和1,4-二咖啡酰-L-赖氨酸。对整合酶抑制剂与2′,3′-二脱氧胞苷、阿司匹林和奈非那韦（蛋白酶抑制剂）的测试表明，对逆转录酶抑制剂耐药病毒具有强大的协同作用。将整合酶抑制剂添加到联合药物疗法中的潜在益处是显著的。
• Dicaffeoyltartaric Acid Analogues Inhibit Human Immunodeficiency Virus Type 1 (HIV-1) Integrase and HIV-1 Replication at Nontoxic Concentrations
  作者：Ryan A. Reinke、Peter J. King、Joseph G. Victoria、Brenda R. McDougall、Guoxiang Ma、Yingqun Mao、Manfred G. Reinecke、W. Edward Robinson

  DOI：10.1021/jm010359d

  日期：2002.8.1

  The human immunodeficiency virus type 1 (HIV-1) is a major health problem worldwide. In this study, 17 analogues of L-chicoric acid, a potent inhibitor of HIV integrase were studied. Of these analogues, five submicromolar inhibitors of integrase were discovered and 13 compounds with activity against integrase at less than 10 muM were identified. Six demonstrated greater than 10-fold selectivity for HIV replication over cellular toxicity. Ten analogues inhibited HIV replication at nontoxic concentrations. Alteration of the linkages between the two bis-catechol rings, including the use of amides, mixed amide esters, cholate, and alkyl bridges, was explored. Amides were as active as esters but were more toxic in tissue culture. Alkyl and cholate bridges were significantly less potent against HIV-1 integrase in vitro and were inactive against HIV-1 replication. Two amino acid derivates and one digalloylderivative of L-chicoric acid (L-CA) showed improved selectivity over L-CA against integration in cell culture. These data suggest that in addition to the bis-catechols and free carboxylic acid groups reported previously, polar linkages are important constituents for optimal activity against HIV-1 integrase and that new derivatives can be developed with increased specificity for integration over HIV entry in vivo.
• NOVEL HIV INTEGRASE INHIBITORS AND HIV THERAPY BASED ON DRUG COMBINATIONS INCLUDING INTEGRASE INHIBITORS
  申请人：The Regents of the University of California

  公开号：EP1063888A1

  公开（公告）日：2001-01-03
• US4708964A
  申请人：——

  公开号：US4708964A

  公开（公告）日：1987-11-24
• [EN] NOVEL HIV INTEGRASE INHIBITORS AND HIV THERAPY BASED ON DRUG COMBINATIONS INCLUDING INTEGRASE INHIBITORS<br/>[FR] NOUVEAUX INHIBITEURS DE VIH INTEGRASE ET TRAITEMENT DU VIH FONDE SUR DES COMBINAISONS DE MEDICAMENTS CONTENANT DES INHIBITEURS D'INTEGRASE
  申请人：THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

  公开号：WO1999048371A1

  公开（公告）日：1999-09-30

  (EN) The present invention includes a group of novel compounds that are demonstrated to potently and selectively inhibit HIV integrase (IN) activity $i(in vitro) and to potently inhibit HIV replication in live, cultured cells at non-toxic concentrations. The novel compounds disclosed include 2,3 -di(3,4- dihydroxydihydroxydihydrocinnamoyl) -L-tartaric acid, 2,3 -di-(3,4-dihydroxybenzoyl) -L-tartaric acid, 2,3 -di-(3,4 -dihydroxyphenylacetyl) -L-tartaric acid , 2,3 -di-(3,4,5 -trihydroxybenzoyl -L-tartaric acid, 2,3-dicaffeoyldiamidopropionic acid, 1,2,-dicaffeoyl -L-glyceric acid, bis, -3,4 -dicaffeoyldiamidobenzoic acid, di-3,4 -dihydroxybenzylidene succinic acid, di-3,4 -dihydrodihydroxybenzylidine succinic acid, 2,3 -dicaffeoyl-L-serine, bis-dicaffeoyl -L-isoserine and 1,4-dicaffeoyl -L-lysine. Tests of integrase inhibitors with 2',3'-dideoxycytidine, zidovudine and nelfinavir (protease inhibitor) indicated a potent synergy against reverse transcriptase inhibitor resistant virus. The potential benefit from the addition of integrase inhibitors to combination drug therapies is significant.(FR) La présente invention concerne un groupe de nouveaux composés qui constituent des inhibiteurs puissants et sélectifs de l'activité de VIH intégrase (IN) $i( in vitro), et des inhibiteurs puissants de la réplication du VIH dans des cellules vivantes de culture à des concentrations non toxiques. Les nouveaux composés renferment de l'acide 2,3 -di(3,4 -dihydroxydidihydroxydihydrocinnamoyl) -L-tartrique, de l'acide 2,3 -di-(3,4 -dihydroxybenzoyl) -L-tartrique, de l'acide 2,3 -di-(3,4 -dihydroxyphénylacétyl) -L-tartrique, de l'acide 2,3 -di(3,4,5 -trihydroxybenzoyl-L-tartrique, de l'acide 2,3 -dicaféyldiamidopropionique, de l'acide 1,2,-dicaféyl-L-glycérique, de l'acide bis,-3,4 -dicaféyldiamidobenzoïque, de l'acide di-3,4 -dihydroxybenzylidène succinique, de l'acide di-3,4 -dihydrodihydroxybenzylidyne succinique, de la 2,3 -dicaféyl-L-sé rine, de la bis-dicaféyl -L-isosérine et de la 1,4 -dicaféyl-L-lysine. Des essais impliquant des inhibiteurs d'intégrase avec la 2',3'-didésoxycytidine, la zidovudine et le nelfinavir (inhibiteur de protéase) ont montré une synergie puissante contre un virus résistant aux inhibiteurs de transcriptase inverse. Les avantages potentiels provenant de l'ajout d'inhibiteurs d'intégrase à des thérapies à combinaison de médicaments sont considérables.