N-{4-[3-(2-amino-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-6-yl)propyl]benzoyl}-L-glutamic acid | 136784-64-0

• 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: N-{4-[3-(2-amino-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-6-yl)propyl]benzoyl}-L-glutamic acid
• 英文别名: (2S)-2-[[4-[3-(2-amino-4-oxo-3H-thieno[2,3-d]pyrimidin-6-yl)propyl]benzoyl]amino]pentanedioic acid
• CAS: 136784-64-0
• 化学式: C₂₁H₂₂N₄O₆S
• 分子量: 458.495
• InChiKey: JPNVUHMAMNATQU-HNNXBMFYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  32
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  199
• 氢给体数：
  5
• 氢受体数：
  8

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  ——	diethyl N-{4-[3-(2-amino-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-6-yl)pentyl]benzoyl}-L-glutamate	1150670-76-0	C25H30N4O6S	514.602

反应信息

• 作为产物：
  描述：

  diethyl N-{4-[3-(2-amino-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-6-yl)pentyl]benzoyl}-L-glutamate 在 水 、 sodium hydroxide 作用下， 以 乙醇 为溶剂， 反应 3.0h， 以96.5%的产率得到N-{4-[3-(2-amino-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-6-yl)propyl]benzoyl}-L-glutamic acid
  参考文献：
  名称：

  Synthesis and Biological Activity of a Novel Series of 6-Substituted Thieno[2,3-d]pyrimidine Antifolate Inhibitors of Purine Biosynthesis with Selectivity for High Affinity Folate Receptors over the Reduced Folate Carrier and Proton-Coupled Folate Transporter for Cellular Entry^†

  摘要：

  A series of seven 2-amino4-oxo-6-substituted thieno[2,3-d]pyrimidines with bridge length variations (from 2 to 8 carbon atoms) were synthesized as selective folate receptor (FR) alpha and beta substrates and as antitumor agents. The syntheses were accomplished from appropriate allylalcohols and 4-iodobenzoate to afford the aldehydes, which were converted to the appropriate 2-amino-4-carbethoxy-5-substituted thiophenes 23-29. Cyclization with chloroformamidine afforded the thieno[2,3-d]pyrimidines 30-36, which were hydrolyzed and coupled with diethyl-L-glutamate, followed by saponification, to give the target compounds 2-8. Compounds 3-6 were potent growth inhibitors (IC50 4.7-334 nM) of human tumor cells (KB and IGROV1) that express FRs. In addition, compounds 3-6 inhibited the growth of Chinese hamster ovary (CHO) cells that expressed FRs but not the reduced folate carrier (RFC) or proton-coupled folate transporter (PCFT). However, the compounds were inactive toward CHO cells that lacked FRs but contained either the RFC or PCFT. By nucleoside and 5-amino-imidazole carboxamide (AICA) protection studies, along with in vitro and in situ enzyme activity assays, the mechanism of antitumor activity was identified as the dual inhibition of glycinamide ribonucleotide formyltransferase and, likely, AICA ribonucleotide formyltransferase. The dual inhibitory activity of the active thieno[2,3-d]pyrimidine antifolates and the FR specificity represent unique mechanistic features for these compounds distinct from all other known antifolates. The potent inhibitory effects of compounds 3-6 toward cells expressing FRs but not PCFT provide direct evidence that cellular uptake of this series of compounds by FRs does not depend on the presence of PCFT and argues that direct coupling between these transporters is not obligatory.

  DOI：

  10.1021/jm8011323

文献信息

• Condensed heterocyclic glutamic acid derivatives, their production and use
  申请人：Takeda Chemical Industries, Ltd.

  公开号：EP0438261A2

  公开（公告）日：1991-07-24

  Novel compounds of the formula: wherein the ring A is a 5-membered ring, provided that, in the case where the ring A is a pyrrole or pyrroline ring, (i) the N atom in the ring has no active proton or (ii) the ring bonds to Z at the -position of the ring;    B is a divalent cyclic or chain group which may be substituted; one of Q¹ and Q² is N, with the other being N or CH; Y is a hydrogen or halogen atom or a group which bonds to the bonding line with a carbon, nitrogen, oxygen or sulfur atom; X is an amino, hydroxyl or mercapto group;    Z is a straight-chain divalent group having a number of atoms of 2 to 5 composed of carbon atoms which each may be substituted, or of carbon atoms which each may be substituted and one hetero atom which may be substituted;    -COOR¹ and -COOR² each is the same as or different from the other and represents a carboxyl group which may be esterified or its salts are produced by reacting compounds of the formula, wherein A, B, Q¹, Q², X, Y, and Z are the same as defined above, with compounds of the formula, wherein -COOR¹ and -COOR² are the same as defined above. The compounds are useful as an antitumor agent.

  式中的新型化合物： 其中环 A 是五元环，条件是，在环 A 是吡咯或吡咯啉环的情况下，(i) 环中的 N 原子没有活泼质子，或 (ii) 环在环的-位与 Z 键合； B 是可被取代的二价环状或链状基团；Q¹ 和 Q² 中的一个是 N，另一个是 N 或 CH；Y 是氢原子或卤素原子或与碳原子、氮原子、氧原子或硫原子键合的基团；X 是氨基、羟基或巯基； Z 是原子数为 2 至 5 的直链二价基团，由各自可被取代的碳原子组成，或由各自可被取代的碳原子和一个可被取代的杂原子组成； -COOR¹和-COOR²各自相同或不同，代表可被酯化的羧基或其盐，通过与式中化合物反应生成、 其中 A、B、Q¹、Q²、X、Y 和 Z 与上式所定义的相同、 其中 -COOR¹ 和 -COOR² 与上述定义相同。 这些化合物可用作抗肿瘤剂。
• Synthesis and Biological Activity of a Novel Series of 6-Substituted Thieno[2,3-<i>d</i>]pyrimidine Antifolate Inhibitors of Purine Biosynthesis with Selectivity for High Affinity Folate Receptors over the Reduced Folate Carrier and Proton-Coupled Folate Transporter for Cellular Entry^†
  作者：Yijun Deng、Xilin Zhou、Sita Kugel Desmoulin、Jianmei Wu、Christina Cherian、Zhanjun Hou、Larry H. Matherly、Aleem Gangjee

  DOI：10.1021/jm8011323

  日期：2009.5.14

  A series of seven 2-amino4-oxo-6-substituted thieno[2,3-d]pyrimidines with bridge length variations (from 2 to 8 carbon atoms) were synthesized as selective folate receptor (FR) alpha and beta substrates and as antitumor agents. The syntheses were accomplished from appropriate allylalcohols and 4-iodobenzoate to afford the aldehydes, which were converted to the appropriate 2-amino-4-carbethoxy-5-substituted thiophenes 23-29. Cyclization with chloroformamidine afforded the thieno[2,3-d]pyrimidines 30-36, which were hydrolyzed and coupled with diethyl-L-glutamate, followed by saponification, to give the target compounds 2-8. Compounds 3-6 were potent growth inhibitors (IC50 4.7-334 nM) of human tumor cells (KB and IGROV1) that express FRs. In addition, compounds 3-6 inhibited the growth of Chinese hamster ovary (CHO) cells that expressed FRs but not the reduced folate carrier (RFC) or proton-coupled folate transporter (PCFT). However, the compounds were inactive toward CHO cells that lacked FRs but contained either the RFC or PCFT. By nucleoside and 5-amino-imidazole carboxamide (AICA) protection studies, along with in vitro and in situ enzyme activity assays, the mechanism of antitumor activity was identified as the dual inhibition of glycinamide ribonucleotide formyltransferase and, likely, AICA ribonucleotide formyltransferase. The dual inhibitory activity of the active thieno[2,3-d]pyrimidine antifolates and the FR specificity represent unique mechanistic features for these compounds distinct from all other known antifolates. The potent inhibitory effects of compounds 3-6 toward cells expressing FRs but not PCFT provide direct evidence that cellular uptake of this series of compounds by FRs does not depend on the presence of PCFT and argues that direct coupling between these transporters is not obligatory.