(R^*)-N-<<2-<(1,1-dimethylethoxy)carbonyl>1,2,3,4-tetrahydro-3-isoquinoinyl>carbonyl>-L-methionine, methyl ester | 166168-88-3

• 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: (R^*)-N-<<2-<(1,1-dimethylethoxy)carbonyl>1,2,3,4-tetrahydro-3-isoquinoinyl>carbonyl>-L-methionine, methyl ester
• 英文别名: (R*)-N-<<2-<(1,1-dimethylethoxy)carbonyl>-1,2,3,4-tetrahydro-3-isoquinolinyl>carbonyl>-L-methionine methyl ester；(S)-tert-butyl 3-(((S)-1-methoxy-4-(methylthio)-1-oxobutan-2-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate；N-((S)-2-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-L-methionine methyl ester；N-(3S-2-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-L-methionine methyl ester；Boc-Tic-Met-OMe；tert-butyl (3S)-3-[[(2S)-1-methoxy-4-methylsulfanyl-1-oxobutan-2-yl]carbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate
• CAS: 166168-88-3
• 化学式: C₂₁H₃₀N₂O₅S
• 分子量: 422.546
• InChiKey: RTLWYVPTMSWNPI-IRXDYDNUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  29
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  110
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (R^*)-N-<<2-<(1,1-dimethylethoxy)carbonyl>1,2,3,4-tetrahydro-3-isoquinoinyl>carbonyl>-L-methionine, methyl ester 在 盐酸 、 三乙胺 作用下， 以 甲醇 、 乙酸乙酯 为溶剂， 反应 241.5h， 生成 (S)-2-((S)-3,3-dimethyl-1-oxo-10,10a-dihydroimidazo[1,5-b]isoquinolin-2(1H,3H,5H)-yl)-4-(methylthio)butanoic acid methyl ester
  参考文献：
  名称：

  2-Substituted (S)-2-(3,3-dimethyl-1-oxo-10,10a-dihydroimidazo[1,5-b]isoquinolin-2(1H,3H,5H)-yl)acetic acids: Conformational prediction, synthesis, anti-thrombotic and vasodilative evaluation

  摘要：

  (S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (TIC) can inhibit thrombosis by inhibiting platelet aggregation. The investigation of amino acids modified TIC reveals that a stretching conformation is critical for high anti-thrombotic activity. The conformational modeling shows that introducing a ring into amino acid modified TIC results in a desirable stretching conformation. According to this hypothesis, we synthesized seventeen novel 2-substituted (S)-2-(3,3-dimethyl-1-oxo-10,10a-dihydroimidazo[1,5-b] isoquinolin-2(1H,3H,5H)-yl)acetic acids (5a-q). In the in vitro anti-platelet aggregation assay, for ADP-induced platelet aggregation the IC50 values of 5a-q are 1.8-3.4-folds lower than that of TIC. In the in vivo anti-thrombotic assay, the effective dose of 5a-q was 167-folds lower than that of TIC. The vessel strip assay showed that 5a-q had mild vasorelaxation activity. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.12.005
• 作为产物：
  描述：

  L-1,2,3,4-四氢异喹啉-3-羧酸盐酸盐 在 4-二甲氨基吡啶 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 sodium hydroxide 作用下， 以 二氯甲烷 为溶剂， 反应 12.5h， 生成 (R^*)-N-<<2-<(1,1-dimethylethoxy)carbonyl>1,2,3,4-tetrahydro-3-isoquinoinyl>carbonyl>-L-methionine, methyl ester
  参考文献：
  名称：

  新型1,2,3,4-四氢异喹啉-3-羧酸衍生物作为氨肽酶N / CD13抑制剂的设计，合成及生物学评价

  摘要：

  设计，合成并测定了一系列新颖的1,2,3,4-四氢异喹啉-3-羧酸衍生物对氨基肽酶N（APN / CD13）和MMP-2的活性。结果表明，大多数化合物对APN的抑制活性均高于MMP-2。在该系列中，化合物12h（IC 50  = 6.28±0.11μM）与Bestatin（IC 50  = 5.55± 0.01μM）表现出相似的抑制活性，并且可以用作新型APN抑制剂作为抗癌剂，用于未来的APN抑制剂开发。

  DOI：

  10.1016/j.bmc.2011.08.041

文献信息

• A class of novel N-(3S-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-l-amino acid derivatives: their synthesis, anti-thrombotic activity evaluation, and 3D QSAR analysis
  作者：Shenling Cheng、Xiaoyi Zhang、Wei Wang、Ming Zhao、Meiqing Zheng、Heng Wei Chang、Jianghui Wu、Shiqi Peng

  DOI：10.1016/j.ejmech.2009.08.002

  日期：2009.12

  To find new anti-thrombotic agents, a natural amino acid was introduced into the 3-position of anti-platelet aggregation active 3S-tetrahydroisoquinoline-3-carboxylic acid (THIQA), and 20 novel dipeptide derivatives, 3S-tetrahydroisoquinoline-3-carboxyamino acids (6a–t), targeting the intestinal peptide transport system were provided. In vitro anti-platelet aggregation assay of 6a–t indicated that

  为了找到新的抗血栓形成剂，将天然氨基酸引入了抗血小板聚集活性3 S-四氢异喹啉-3-羧酸（THIQA）的3位，以及20种新型二肽衍生物3 S-四氢异喹啉-3提供了靶向肠肽转运系统的-羧基氨基酸（6a - t）。6a - t的体外抗血小板凝集试验表明，它们抑制二磷酸腺苷（ADP），花生四烯酸（AA），血小板活化因子（PAF）和凝血酶（TH）诱导的血小板凝集的效力高于THIQA和6a – t的体内抗血栓形成测定提示它们在大鼠中抑制血栓形成的能力也高于THIQA。根据基于MFA的Cerius2 QSAR模块，使用训练/测试集6a，b，d，g – p / 6c，e，f，q和训练/测试集6a – p / 6q – t，两个方程式（r， 0.984和0.996）建立了与6a - t的体内或体外活性相关的结构。
• Development of Highly Potent Inhibitors of Ras Farnesyltransferase Possessing Cellular and <i>in Vivo </i>Activity
  作者：Katerina Leftheris、Toni Kline、Gregory D. Vite、Young H. Cho、Rajeev S. Bhide、Dinesh V. Patel、Manorama M. Patel、Robert J. Schmidt、Harold N. Weller、Mary L. Andahazy、Joan M. Carboni、Johnni L. Gullo-Brown、Francis Y. F. Lee、Carol Ricca、William C. Rose、Ning Yan、Mariano Barbacid、John T. Hunt、Chester A. Meyers、Bernd R. Seizinger、Robert Zahler、Veeraswamy Manne

  DOI：10.1021/jm950642a

  日期：1996.1.1

  Analogs of CVFM (a known nonsubstrate farnesyltransferase (FT) inhibitor derived from a CA1A2X sequence where C is cysteine, A is an aliphatic residue, and X is any residue) were prepared where phenylalanine was replaced by (Z)-dehydrophenylalanine, 2-aminoindan-2-carboxylate, 1,2,3,4-tetrahydroisoquinoline-3-carboxylate (Tic), and indoline-2-carboxylate. The greatest improvement in FT inhibitory potency

  制备了CVFM（衍生自CA1A2X序列的已知非底物法尼基转移酶（FT）抑制剂的类似物，其中C为半胱氨酸，A为脂族残基，X为任何残基），其中苯丙氨酸被（Z）-脱氢苯丙氨酸，2-氨基茚满取代-2-羧酸盐，1,2,3,4-四氢异喹啉-3-羧酸盐（Tic）和二氢吲哚-2-羧酸盐。对于Tic衍生物（IC50 = 1 nM），观察到了FT抑制能力的最大改善。然而，该化合物在阻断致癌Ras诱导的NIH-3T3成纤维细胞转化方面无效。制备了其中并入了Cys-Val亚甲胺等排体和Tic替代物的化合物。该衍生物抑制FT的IC50为0.6 nM，并且在5 microM时抑制了稳定转化的NIH-3T3成纤维细胞的不依赖贴壁的生长。用叔丁基取代该衍生物的A1侧链，并用谷氨酰胺取代X位置，得到的衍生物的IC50为2.8 nM，EC50为0.19 microM，比（S *，R * ）-N-[[2- [N-（2-氨基-3-巯基丙基）-L-戊基]
• Potent, Cell Active, Non-Thiol Tetrapeptide Inhibitors of Farnesyltransferase
  作者：John T. Hunt、Ving G. Lee、Katerina Leftheris、Bernd Seizinger、Joan Carboni、John Mabus、Carol Ricca、Ning Yan、Veeraswamy Manne

  DOI：10.1021/jm9507284

  日期：1996.1.1

  CAAX-based farnesyltransferase inhibitors contain a thiol functionality. We report that attachment of the 4-imidazolyl group, via 1-, 2-, or 3-carbon alkyl or alkanoyl spacers, to Val-Tic-Met or tLeu-Tic-Gln provides potent FT inhibitors. (R*)-N-[[1,2,3,4-Tetrahydro-2-[N-[2-(1H-imidazol-4-yl)ethyl] -L-valyl]-3-isoquinolinyl]carbonyl]-L-methionine ([imidazol- 4-yl-ethyl]-Val-Tic-Met), with FT IC50 = 0

  以前报道的所有基于CAAX的法呢基转移酶抑制剂均含有硫醇官能团。我们报告说，通过1-，2-或3-碳烷基或烷酰基间隔基将4-咪唑基连接到Val-Tic-Met或tLeu-Tic-Gln提供了有效的FT抑制剂。（R *）-N-[[[1,2,3,4-四氢-2- [N- [2-（1H-咪唑-4-基）乙基] -L-戊基] -3-异喹啉基]羰基] FT IC50 = 0.79 nM的-L-甲硫氨酸（[咪唑-4-乙基-乙基] -Val-Tic-Met）在没有前药形成的情况下显示出强力的细胞活性（SAG EC50 = 3.8μM）。
• 2-Substituted (S)-2-(3,3-dimethyl-1-oxo-10,10a-dihydroimidazo[1,5-b]isoquinolin-2(1H,3H,5H)-yl)acetic acids: Conformational prediction, synthesis, anti-thrombotic and vasodilative evaluation
  作者：Hong Wang、Le Peng、Ming Zhao、Jiawang Liu、Xiaoyi Zhang、Yuji Wang、Jianhui Wu、Li Li、Shiqi Peng

  DOI：10.1016/j.bmc.2010.12.005

  日期：2011.1

  (S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (TIC) can inhibit thrombosis by inhibiting platelet aggregation. The investigation of amino acids modified TIC reveals that a stretching conformation is critical for high anti-thrombotic activity. The conformational modeling shows that introducing a ring into amino acid modified TIC results in a desirable stretching conformation. According to this hypothesis, we synthesized seventeen novel 2-substituted (S)-2-(3,3-dimethyl-1-oxo-10,10a-dihydroimidazo[1,5-b] isoquinolin-2(1H,3H,5H)-yl)acetic acids (5a-q). In the in vitro anti-platelet aggregation assay, for ADP-induced platelet aggregation the IC50 values of 5a-q are 1.8-3.4-folds lower than that of TIC. In the in vivo anti-thrombotic assay, the effective dose of 5a-q was 167-folds lower than that of TIC. The vessel strip assay showed that 5a-q had mild vasorelaxation activity. (C) 2010 Elsevier Ltd. All rights reserved.
• Design, synthesis and biological evaluation of novel 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as aminopeptidase N/CD13 inhibitors
  作者：Xiaopan Zhang、Jian Zhang、Lei Zhang、Jinghong Feng、Yingying Xu、Yumei Yuan、Hao Fang、Wenfang Xu

  DOI：10.1016/j.bmc.2011.08.041

  日期：2011.10

  A series of novel 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were designed, synthesized and assayed for their activities against aminopeptidase N (APN/CD13) and MMP-2. The results showed that most compounds exhibited higher inhibitory activities against APN than that of MMP-2. Within this series, compound 12h (IC50 = 6.28 ± 0.11 μM) showed similar inhibitory activities compared with

  设计，合成并测定了一系列新颖的1,2,3,4-四氢异喹啉-3-羧酸衍生物对氨基肽酶N（APN / CD13）和MMP-2的活性。结果表明，大多数化合物对APN的抑制活性均高于MMP-2。在该系列中，化合物12h（IC 50  = 6.28±0.11μM）与Bestatin（IC 50  = 5.55± 0.01μM）表现出相似的抑制活性，并且可以用作新型APN抑制剂作为抗癌剂，用于未来的APN抑制剂开发。