2,3-Bis-[(E)-3-(3,4-dihydroxy-phenyl)-acryloylamino]-propionic acid

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 2,3-Bis-[(E)-3-(3,4-dihydroxy-phenyl)-acryloylamino]-propionic acid
• 英文别名: 2,3-bis[[(E)-3-(3,4-dihydroxyphenyl)prop-2-enoyl]amino]propanoic acid
• 化学式: C₂₁H₂₀N₂O₈
• 分子量: 428.398
• InChiKey: PECSAFQUPKTPTO-FCXRPNKRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  31
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  176
• 氢给体数：
  7
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  methyl 2,3-bis[[(E)-3-[3,4-bis(methoxycarbonyloxy)phenyl]prop-2-enoyl]amino]propanoate 在 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 2.5h， 以9 mg的产率得到2,3-Bis-[(E)-3-(3,4-dihydroxy-phenyl)-acryloylamino]-propionic acid
  参考文献：
  名称：

  Design, synthesis, and biological evaluation of chicoric acid analogs as inhibitors of HIV-1 integrase

  摘要：

  A series of analogs of the potent HIV-1 integrase (HIV IN) inhibitor chicoric acid (CA) was designed with the intention of ameliorating some of the parent natural product's undesirable properties, in particular its toxicity, instability, and poor membrane permeability. More than 70 analogs were synthesized and assayed for three types of activity: (1) the ability to inhibit 3'-end processing and strand transfer reactions using recombinant HIV IN in vitro, (2) toxicity against the CD4+ lymphoblastoid cell line, MT2, and (3) anti-HIV activity against HIVLAI. CA analogs lacking one of the carboxyl groups of CA and with 3,4,5-trihydroxycinnamoyl sidechains in place of the caffeoyl group of CA exhibited the most potent inhibition of HIV replication and end-processing activity. Galloyl-substituted derivatives also displayed very potent in vitro and in vivo activities, in most cases exceeding the inhibitory effects of CA itself. Conversely, analogous monocarboxy caffeoyl analogs exhibited only modest inhibition, while the corresponding 3,4-dihydroxybenzoyl-substituted compounds were devoid of activity. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2006.02.030

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。
• 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
• [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.
• Design, synthesis, and biological evaluation of chicoric acid analogs as inhibitors of HIV-1 integrase
  作者：Trevor T. Charvat、Deborah J. Lee、W. Edward Robinson、A. Richard Chamberlin

  DOI：10.1016/j.bmc.2006.02.030

  日期：2006.7

  A series of analogs of the potent HIV-1 integrase (HIV IN) inhibitor chicoric acid (CA) was designed with the intention of ameliorating some of the parent natural product's undesirable properties, in particular its toxicity, instability, and poor membrane permeability. More than 70 analogs were synthesized and assayed for three types of activity: (1) the ability to inhibit 3'-end processing and strand transfer reactions using recombinant HIV IN in vitro, (2) toxicity against the CD4+ lymphoblastoid cell line, MT2, and (3) anti-HIV activity against HIVLAI. CA analogs lacking one of the carboxyl groups of CA and with 3,4,5-trihydroxycinnamoyl sidechains in place of the caffeoyl group of CA exhibited the most potent inhibition of HIV replication and end-processing activity. Galloyl-substituted derivatives also displayed very potent in vitro and in vivo activities, in most cases exceeding the inhibitory effects of CA itself. Conversely, analogous monocarboxy caffeoyl analogs exhibited only modest inhibition, while the corresponding 3,4-dihydroxybenzoyl-substituted compounds were devoid of activity. (c) 2006 Elsevier Ltd. All rights reserved.