(S)-2-({5-[4-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)but-1-ynyl]thiophene-2-carbonyl}amino)pentanedioic acid diethyl ester | 1207641-10-8

• 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: (S)-2-({5-[4-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)but-1-ynyl]thiophene-2-carbonyl}amino)pentanedioic acid diethyl ester
• 英文别名: diethyl (2S)-2-[[5-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-6-yl)but-1-ynyl]thiophene-2-carbonyl]amino]pentanedioate
• CAS: 1207641-10-8
• 化学式: C₂₄H₂₇N₅O₆S
• 分子量: 513.574
• InChiKey: JJKYLQWXHQKRKE-KRWDZBQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  36
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  193
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (S)-2-({5-[4-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)but-1-ynyl]thiophene-2-carbonyl}amino)pentanedioic acid diethyl ester 在 sodium hydroxide 、 盐酸 作用下， 以 甲醇 、 水 为溶剂， 反应 16.0h， 以95%的产率得到(S)-2-({5-[4-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]-pyrimidin-6-yl)but-1-ynyl]thiophene-2-carbonyl}amino)-pentanedioic acid
  参考文献：
  名称：

  Synthesis and Biological Activity of 6-Substituted Pyrrolo[2,3-d]pyrimidine Thienoyl Regioisomers as Inhibitors of de Novo Purine Biosynthesis with Selectivity for Cellular Uptake by High Affinity Folate Receptors and the Proton-Coupled Folate Transporter over the Reduced Folate Carrier

  摘要：

  We previously reported the selective transport of classical 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidines with a thienoyl-for-benzoyl-substituted side chain and a three- (3a) and four-carbon (313) bridge. Compound 3a was more potent than 3b against tumor cells. While 3b was completely selective for transport by folate receptors (FRs) and the proton-coupled folate transporter (PCFT) over the reduced folate carrier (RFC), 3a was not. To determine if decreasing the distance between the bicyclic scaffold and L-glutamate in 3b would preserve transport selectivity and potency against human tumor cells, 3b regioisomers with [1,3] (7 and 8) and [1,2] (4, 5, and 6) substitutions on the thienoyl ring and with acetylenic insertions in the four-atom bridge were synthesized and evaluated. Compounds 7 and 8 were potent nanomolar inhibitors of KB and IGROV1 human tumor cells with complete selectivity for FR alpha and PCFT over RFC.

  DOI：

  10.1021/jm201688n
• 作为产物：
  描述：

  2-amino-6-(but-3-yn-1-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 、 N-(2-bromothieno-5-yl)-L-glutamic acid diethyl ester 在 copper(l) iodide 、 四(三苯基膦)钯 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 以75%的产率得到(S)-2-({5-[4-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)but-1-ynyl]thiophene-2-carbonyl}amino)pentanedioic acid diethyl ester
  参考文献：
  名称：

  新型6-取代吡咯并[2,3-d]嘧啶噻吩基抗叶酸抑制剂的合成和抗肿瘤活性，具有选择性高亲和力叶酸受体和质子偶联叶酸转运蛋白在细胞进入的还原叶酸载体上的嘌呤生物合成

  摘要：

  合成了具有噻吩酰基侧链和 4 到 6 个碳桥长度的2-氨基-4-氧代-6-取代的吡咯并[2,3- d ]嘧啶（化合物1 - 3）作为叶酸受体 (FR) 的底物和质子偶联叶酸转运蛋白 (PCFT)。乙炔羧酸转化为α-溴甲基酮并与2,4-二氨基-6-羟基嘧啶缩合得到6-取代的吡咯并[2,3- d ]嘧啶。薗头与（耦合小号）-2 - [（5-溴-噻吩-2-羰基） -氨基] -戊二酸二乙酯，随后氢化和皂化，得到1 - 3。化合物1和2有效抑制表达 FRα、减少叶酸载体 (RFC) 和 PCFT 的 KB 和 IGROV1 人类肿瘤细胞。类似物对 FR 和 PCFT 比 RFC 具有选择性。甘氨酰胺核糖核苷酸甲酰转移酶是主要的细胞靶标。在具有 KB 肿瘤的 SCID 小鼠中，1对早期（3.5 log 杀死，1/5 治愈）和晚期（3.7 log 杀死，4/5 完全缓解）阶段的肿瘤具有高度活性。我们的结果表明，由于

  DOI：

  10.1021/jm9015729

文献信息

• SELECTIVE PROTON COUPLED FOLATE TRANSPORTER AND FOLATE RECEPTOR, AND GARFTASE INHIBITOR COMPOUNDS AND METHODS OF USING THE SAME
  申请人：Gangjee Aleem

  公开号：US20100081676A1

  公开（公告）日：2010-04-01

  Fused cyclic pyrimidine compounds, including tautomers thereof, and pharmaceutically acceptable salts, prodrugs, solvates and hydrates thereof, are disclosed having the general Formula I: These compounds are useful in methods for treating cancer, selectively targeting cancerous cells via the proton coupled folate transporter, folate receptor alpha, and/or folate receptor beta pathways, inhibiting GARFTase in cancerous cells, and selectively targeting activated macrophages in a patient having an autoimmune disease, such as rheumatoid arthritis.

  揭示了融合的环状嘧啶化合物，包括其互变异构体，以及药用可接受的盐、前药、溶剂合物和水合物，其具有一般的化学式I：这些化合物在治疗癌症的方法中是有用的，通过质子耦合叶酸转运蛋白、叶酸受体α和/或叶酸受体β通路选择性地靶向癌细胞，抑制癌细胞中的GARFTase，并选择性地靶向患有自身免疫疾病（如类风湿性关节炎）的患者中激活的巨噬细胞。
• Selective proton coupled folate transporter and folate receptor, and GARFTase inhibitor compounds and methods of using the same
  申请人：Duquesne University of the Holy Spirit

  公开号：US10000498B2

  公开（公告）日：2018-06-19

  Fused cyclic pyrimidine compounds, including tautomers thereof, and pharmaceutically acceptable salts, prodrugs, solvates and hydrates thereof, are disclosed having the general Formula I: These compounds are useful in methods for treating cancer, selectively targeting cancerous cells via the proton coupled folate transporter, folate receptor alpha, and/or folate receptor beta pathways, inhibiting GARFTase in cancerous cells, and selectively targeting activated macrophages in a patient having an autoimmune disease, such as rheumatoid arthritis.

  本研究公开了具有通式 I 的融合环嘧啶化合物（包括其同系物）及其药学上可接受的盐、原药、溶液和水合物： 这些化合物可用于治疗癌症，通过质子偶联叶酸转运体、叶酸受体α和/或叶酸受体β途径选择性靶向癌细胞，抑制癌细胞中的GARFT酶，以及选择性靶向患有自身免疫性疾病（如类风湿性关节炎）的患者中的活化巨噬细胞。
• Selective proton coupled folate transporter and folate receptor, and garftase inhibitor compounds and methods of using the same
  申请人：Duquesne University of the Holy Spirit

  公开号：US11053252B2

  公开（公告）日：2021-07-06

  Fused cyclic pyrimidine compounds, including tautomers thereof, and pharmaceutically acceptable salts, prodrugs, solvates and hydrates thereof, are disclosed having the general Formula I: These compounds are useful in methods for treating cancer, selectively targeting cancerous cells via the proton coupled folate transporter, folate receptor alpha, and/or folate receptor beta pathways, inhibiting GARFTase in cancerous cells, and selectively targeting activated macrophages in a patient having an autoimmune disease, such as rheumatoid arthritis.

  本研究公开了具有通式 I 的融合环嘧啶化合物（包括其同系物）及其药学上可接受的盐、原药、溶液和水合物： 这些化合物可用于治疗癌症，通过质子偶联叶酸转运体、叶酸受体α和/或叶酸受体β途径选择性靶向癌细胞，抑制癌细胞中的GARFT酶，以及选择性靶向患有自身免疫性疾病（如类风湿性关节炎）的患者中的活化巨噬细胞。
• EP2995199A1
  申请人：——

  公开号：EP2995199A1

  公开（公告）日：2016-03-16
• Selective Proton Coupled Folate Transporter and Folate Receptor, and Garftase Inhibitor Compounds and Methods of Using the Same
  申请人：Duquesne University of the Holy Spirit

  公开号：US20170114066A1

  公开（公告）日：2017-04-27

  Fused cyclic pyrimidine compounds, including tautomers thereof, and pharmaceutically acceptable salts, prodrugs, solvates and hydrates thereof, are disclosed having the general Formula I: These compounds are useful in methods for treating cancer, selectively targeting cancerous cells via the proton coupled folate transporter, folate receptor alpha, and/or folate receptor beta pathways, inhibiting GARFTase in cancerous cells, and selectively targeting activated macrophages in a patient having an autoimmune disease, such as rheumatoid arthritis.