bis(diphenylmethyl) L-tartrate | 85488-41-1

• 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: bis(diphenylmethyl) L-tartrate
• 英文别名: dibenzhydryl-L-tartrate；diphenylmethyl tartrate；dibenzhydryl (2R,3R)-2,3-dihydroxybutanedioate
• CAS: 85488-41-1
• 化学式: C₃₀H₂₆O₆
• 分子量: 482.533
• InChiKey: PPLCSEXTISFQTH-CLJLJLNGSA-N

物化性质

• 沸点：
  630.6±55.0 °C(Predicted)
• 密度：
  1.271±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  36
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  93.1
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  bis(diphenylmethyl) L-tartrate 在 吡啶 、 sodium carbonate 作用下， 以 四氢呋喃 、 甲醇 、 苯 为溶剂， 反应 2.5h， 生成 bis(diphenylmethyl) dicaffeoyl-L-tartrate
  参考文献：
  名称：

  Structure−Activity Relationships:  Analogues of the Dicaffeoylquinic and Dicaffeoyltartaric Acids as Potent Inhibitors of Human Immunodeficiency Virus Type 1 Integrase and Replication

  摘要：

  The dicaffeoylquinic acids (DCQAs) and dicaffeoyltartaric acids (DCTAs) are potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) integrase. They also inhibit HIV-1 replication at nontoxic concentrations; Since integrase is an excellent target for anti-HIV therapy, structure-activity relationships were employed to synthesize compounds with: (1) improved potency against HIV-1 integrase, (2) improved anti-HIV effect in tissue culture, and (3) increased selectivity as indicated by low cellular toxicity. Thirty-four analogues of the DCTAs and DCQAs were synthesized and tested for cell toxicity, anti-HIV activity, and inhibition of HIV-1 integrase. Seventeen of the 34 analogues had potent activity against HIV-1 integrase ranging from 0.07 to >10 mu M. Seventeen analogues that were synthesized or purchased had no inhibitory activity against integrase at concentrations of 25 mu M. Of the biologically active analogues, 7 of the 17 inhibited HIV replication at nontoxic concentrations. The most potent compounds were D-chicoric acid, meso-chicoric acid, bis(3,4-dihydroxydihydrocinnamoyl)-L-tartaric acid, digalloyl-L-tartaric acid, bis(3,4-dihydroxybenzoyl)-L-tartaric acid, dicaffeoylglyceric acid, and bis(3,4-dihydroxyphenylacetyl)-L-tartaric acid. Anti-HIV activity of the active compounds in tissue culture ranged from 35 to 0.66 mu M. Structure-activity relationships demonstrated that biscatechol moieties were absolutely required for inhibition of integrase, while at least one free carboxyl group was required for anti-HIV activity. These data demonstrate that analogues of the DCTAs and the DCQAs can be synthesized which have improved activity against HIV integrase.

  DOI：

  10.1021/jm9804735
• 作为产物：
  描述：

  二苯甲酮腙 在 manganese(IV) oxide 、 magnesium sulfate 作用下， 以 二氯甲烷 为溶剂， 生成 bis(diphenylmethyl) L-tartrate
  参考文献：
  名称：

  FR258900酒石酸类似物的合成及其作为糖原磷酸化酶抑制剂的评价

  摘要：

  合成了二-O-肉桂酸化，-p-香豆酰化和-阿魏酸化的d-，l-和内消旋酒石酸作为天然产物FR258900的类似物，FR258900是一种具有体内抗高血糖活性的糖原磷酸化酶（GP）抑制剂。新化合物在低微摩尔范围内抑制兔肌肉GP，并与酶的变构位点结合。最好的抑制剂是2,3-二-O-阿魏酰基内消旋酒石酸，抗AMP的K i值为2.0μM （竞争性），抗葡萄糖-1-磷酸的K i值为3.36μM （非竞争性）。

  DOI：

  10.1016/j.bmcl.2013.01.042

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。
• Synthetic studies on tabtoxin. Synthesis of a naturally occuring inhibitor of glutamine synthetase, tabtoxinine-β-lactam, and analogues
  作者：Jack E. Baldwin、Masami Otsuka、Philip M. Wallace

  DOI：10.1016/s0040-4020(01)87377-4

  日期：1986.1

  (±)- Tabtoxinine-β-lactam 2, a potent inhibitor of glutamine synthetase, and related compounds, have been synthesised by a cycloaddition approach. The cycloaddition of an acylnitroso compound to cyolohexadienes proceeded regioselectively to give the bicyclic, ester 8 (X=CO2Et) or nitrile 24. These were converted into the cyclic diacids 15, 17, 27 and 33 by permanganate oxidation. A benzyl chloroformate

  已经通过环加成法合成了谷氨酰胺合成酶的有效抑制剂（±）-毒素-β-内酰胺2和相关化合物。酰基亚硝基化合物与环己二烯的环加成反应选择性进行，得到双环酯8（X = CO 2Et）或腈24。通过高锰酸盐氧化将其转化为环状二酸15、17、27和33。开发了氯甲酸苄酯介导的酯化方法，以区分两个羧基以提供单酯16a，19、28a和34。用氯甲酸苄酯处理羟基二酸20得到了螺旋β-内酯11。β-氨基酸的环化29和35之后氢化，分别得到（±）-塔宾毒素-β-内酰胺2和甲氧基衍生物5。备选地，通过将​​硝酮39区域选择性地进行1,3-偶极环加成，将螺环β-内酰胺45a和45b以41:59的比例获得到外亚甲基β-内酰胺44上。
• Design, Synthesis, and Biological Evaluation of Novel Hybrid Dicaffeoyltartaric/Diketo Acid and Tetrazole-Substituted <scp>l</scp>-Chicoric Acid Analogue Inhibitors of Human Immunodeficiency Virus Type 1 Integrase
  作者：David C. Crosby、Xiangyang Lei、Charles G. Gibbs、Brenda R. McDougall、W. Edward Robinson、Manfred G. Reinecke

  DOI：10.1021/jm1010594

  日期：2010.11.25

  Fourteen analogues of the anti-HIV-1 integrase (IN) inhibitor L-chicoric acid (L-CA) were prepared. Their IC50 values for 3'-end processing and strand transfer against recombinant HIV-1 IN were determined in vitro, and their cell toxicities and EC50 against HIV-1 were measured in cells (ex vivo). Compounds 1-6 are catechol/beta-diketoacid hybrids, the majority of which exhibit submicromolar potency against 3'-end processing and strand transfer, though only with modest antiviral activities. Compounds 7-10 are L-CA/p-fluorobenzylpyrroloyl hybrids, several of which were more potent against strand transfer than 3'-end processing, a phenomenon previously attributed to the beta-diketo acid pharmacophore. Compounds 11-14 are tetrazole bioisosteres of L-CA and its analogues, whose in vitro potencies were comparable to L-CA but with enhanced antiviral potency. The trihydroxyphenyl analogue 14 was 30-fold more potent than L-CA at relatively nontoxic concentrations. These data indicate that L-CA analogues are attractive candidates for development into clinically relevant inhibitors of HIV-1 IN.
• 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