(R)-2-((S)-4-氨基-5-叔丁氧基-5-氧代戊酰胺基)戊二酸二叔丁酯 | 145817-20-5

• 物质功能分类: 有机原料 - 羧酸类化合物及衍生物 - 羧酸酯及其衍生物
• 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
• 中文名称: (R)-2-((S)-4-氨基-5-叔丁氧基-5-氧代戊酰胺基)戊二酸二叔丁酯
• 英文名称: tri-tert-butyl L-γ-glutamyl-D-glutamate
• 英文别名: (R)-di-tert-butyl 2-((S)-4-amino-5-tert-butoxy-5-oxopentanamido)pentanedioate；ditert-butyl (2R)-2-[[(4S)-4-amino-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoyl]amino]pentanedioate
• CAS: 145817-20-5
• 化学式: C₂₂H₄₀N₂O₇
• 分子量: 444.569
• InChiKey: KBONZTYAIRBOLZ-LSDHHAIUSA-N

物化性质

• 沸点：
  548.0±50.0 °C(Predicted)
• 密度：
  1.077±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  31
• 可旋转键数：
  15
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.82
• 拓扑面积：
  134
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (R)-2-((S)-4-氨基-5-叔丁氧基-5-氧代戊酰胺基)戊二酸二叔丁酯 在 氰基磷酸二乙酯 、 三乙胺 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 5.0h， 生成 (2R)-2-[[(4S)-4-[[4-[(2-amino-4-oxo-3,6,7,8-tetrahydrocyclopenta[g]quinazolin-6-yl)-prop-2-ynylamino]benzoyl]amino]-4-carboxybutanoyl]amino]pentanedioic acid
  参考文献：
  名称：

  使用基于环戊达[g]喹唑啉的胸苷酸合酶抑制剂靶向α-叶酸受体。

  摘要：

  据报道，α-FR在许多癌中过表达，特别是在卵巢癌和子宫癌中。在过去的十年中，已经利用α-FR在某些肿瘤中与正常组织中的高表达来将叶酸介导的大分子，抗癌药，显像剂和核酸靶向癌细胞。据报道，CB300638是一种基于环戊基[g]喹唑啉的胸苷酸合酶（TS）抑制剂，对受体具有高亲和力，并且对过表达α-FR的肿瘤细胞系具有高度选择性。在这项研究中，针对TS抑制作用，研究了分子的结构特征，尤其是在2位修饰的分子，与新转染的A431细胞相比，A431-FBP细胞（用人α-FR转染）对α-FR的亲和力和降低的叶酸载体（RFC）和活性。利用多步序列合成了化合物1a，b，2a，b和3a，b。发现2-取代基不影响对α-FR的亲和力；反之，α-FR不受影响。但是，它极大地影响了对A431-FBP细胞的选择性，并表明除了TS抑制作用和α-FR亲和力以外，还有其他因素对于这些化合物的活性也很重要。与A431细胞相比，

  DOI：

  10.1016/j.bmc.2006.03.001
• 作为产物：
  描述：

  D-谷氨酸 在 palladium on activated charcoal N-甲基吗啉 、 硫酸 、 氢气 、 氯甲酸异丁酯 作用下， 以 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 76.83h， 生成 (R)-2-((S)-4-氨基-5-叔丁氧基-5-氧代戊酰胺基)戊二酸二叔丁酯
  参考文献：
  名称：

  喹唑啉抗叶酸胸苷酸合酶抑制剂：2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid（ICI 198583）的γ-连接的LD，DD和DL二肽类似物。

  摘要：

  描述了γ-连接的2-脱氨基-2-甲基-N10-炔丙基-5,8-二氮杂萘甲酸的LD，DD和DL二肽类似物的合成（ICI 198583）。合成这些分子的通用方法包括采用溶液相肽合成法制备二肽衍生物，然后通过氰基磷酸二乙酯（DEPC）活化将二肽游离碱与适当的蝶酸类似物缩合。在最后一步中，通过三氟乙酸（TFA）水解除去叔丁酯。ZL-Glu-OBut-γ-D-Ala-OBut例如是由N-（苄氧羰基）-L-谷氨酸的α-叔丁基和D-丙氨酸的叔丁基通过异丁基-混合酸酐偶联制备的。通过催化氢解除去Z-基团，并通过DEPC偶联将所得的二肽游离碱与2-脱氨基-2-甲基-N10-炔丙基-5,8-二脱氮杂戊酸缩合。最后，通过TFA水解除去叔丁酯，得到ICI198583-γ-D-Ala。测试这些化合物作为胸苷酸合酶和L1210细胞生长的抑制剂。发现与γ-连接的LD二肽具有良好的酶和生长抑制活性，最好的例子是Glu-γ-D-Glu衍生物35（Ki

  DOI：

  10.1021/jm950471+

文献信息

• Cyclopenta[g]quinazoline-based antifolates: the effect of the chirality at the 6-position on the inhibition of thymidylate synthase (TS)
  作者：V. Bavetsias、J.H. Marriott、D.S. Theti、J.C. Melin、S.C. Wilson、A.L. Jackman

  DOI：10.1016/s0960-894x(01)00612-6

  日期：2001.12

  inhibitors of thymidylate synthase (TS) possess a chiral centre at the 6-position of the molecule. The effect of this chirality on the inhibition of TS was investigated by synthesising compounds 6S-1a-c, 6R-1a-c. It was shown, in particular with the diastereoisomers 6S-1c, 6R-1c, that the inhibitory activity against TS is mainly due to the 6S diastereoisomer rather than the 6R diastereoisomer, which is

  胸苷酸合酶（TS）的基于环戊[g]喹唑啉的抑制剂在分子的6-位具有手性中心。通过合成化合物6S-1a-c，6R-1a-c，研究了这种手性对TS抑制的影响。已显示，特别是对于非对映异构体6S-1c，6R-1c，对TS的抑制活性主要归因于6S非对映异构体，而不是实际上无活性的6R非对映异构体。
• Non-classical antifolates
  申请人：THE TRUSTEES OF PRINCETON UNIVERSITY

  公开号：EP0761668B1

  公开（公告）日：2002-01-30
• Design and Synthesis of Cyclopenta[<i>g</i>]quinazoline-Based Antifolates as Inhibitors of Thymidylate Synthase and Potential Antitumor Agents^,
  作者：Vassilios Bavetsias、Jonathan H. Marriott、Camille Melin、Rosemary Kimbell、Zbigniew S. Matusiak、F. Thomas Boyle、Ann L. Jackman

  DOI：10.1021/jm991119p

  日期：2000.5.1

  Following the development of raltitrexed, the synthesis of nonpolyglutamatable inhibitors of TS that do not use the reduced folate carrier (RFC) for cellular entry should provide compounds which overcome mechanisms of resistance to folate-based inhibitors of TS that are associated with decreased/altered folylpolyglutamate synthetase (FPGS) expression and/or an impaired RFC. Examination of a computer graphics model of the humanized Escherichia coli TS enzyme with quinazoline inhibitors of TS, such as 1 bound in the active site of the enzyme, suggested that conformational restriction introduced by bridging the C9 with C7 to form a pentacycle may be beneficial for binding to TS. That led to the synthesis of a series of potent cyclopenta[g]quinazoline-based inhibitors of the enzyme in which the glutamyl residue associated with classical antifolates was replaced with a variety of glutamate-derived ligands; the most potent inhibitor being the L-Glu-gamma-D-GluT(alpha) derivative 7j. In the mouse L1210:1565 cell line (mutant RFC), the majority of these compounds had activity equal or only slightly greater compared with the parental L1210 cell line, indicating a reduced dependence on the RFC for cellular uptake in the L1210 cell line.
• Development and Binding Mode Assessment of <i>N</i>-[4-[2-Propyn-1-yl[(6<i>S</i>)-4,6,7,8-tetrahydro-2-(hydroxymethyl)-4-oxo-3<i>H</i>-cyclopenta[<i>g</i>]quinazolin-6-yl]amino]benzoyl]-<scp>l</scp>-γ-glutamyl-<scp>d</scp>-glutamic Acid (BGC 945), a Novel Thymidylate Synthase Inhibitor That Targets Tumor Cells
  作者：Anna Tochowicz、Sean Dalziel、Oliv Eidam、Joseph D. O’Connell、Sarah Griner、Janet S. Finer-Moore、Robert M. Stroud

  DOI：10.1021/jm400490e

  日期：2013.7.11

  N-[4-[2-Propyn-1-yl[(6S)-4,6,7,8-tetrahydro-2-(hydroxymethyl)-4-oxo-3H-cyclopent[g]quinazolin-6-yl]amino]benzoyl]-L-gamma-glutamyl-D-glutamic acid 1 (BGC 945, now known as ONX 0801); is a small molecule thymidylate synthase (TS) inhibitor discovered at the Institute of Cancer Research in London. It is licensed by Onyx Pharmaceuticals and is in phase,1 clinical studies. It is a novel antifolate drug resembling TS inhibitors plevitrexed and raltitrexed that combines enzymatic inhibition of thymidylate synthase with alpha-folate receptor-mediated targeting of tumor cells. Thus, it has potential for efficacy with lower toxicity due to selective intracellular accumulation through alpha-folate receptor (alpha-FR) transport. The alpha-FR, a cell-surface receptor glycoprotein, which is overexpressed mainly in ovarian and lung cancer tumors, has an affinity for 1 similar to that for its natural ligand, folic acid. This study describes a novel synthesis of 1, an X-ray crystal structure of its complex with Escherichia coli TS and 2'-deoxyuridine-5'-monophosphate, and a model for a similar complex with human TS.
• US5786358A
  申请人：——

  公开号：US5786358A

  公开（公告）日：1998-07-28