4-[4-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-6-yl)butyl]benzoic acid | 863767-93-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并嘧啶类
• 英文名称: 4-[4-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-6-yl)butyl]benzoic acid
• 英文别名: 4-[4-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)butyl]benzoic acid
• CAS: 863767-93-5
• 化学式: C₁₇H₁₈N₄O₃
• 分子量: 326.355
• InChiKey: YDCARMLEUJTVJZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  24.0
• 可旋转键数：
  6.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  124.86
• 氢给体数：
  4.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  4-[4-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-6-yl)butyl]benzoic acid 在 sodium hydroxide 、 三乙胺 、 氯甲酸异丁酯 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 58.5h， 生成 N-{4-[4-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)butyl]benzoyl}-L-glutamic acid
  参考文献：
  名称：

  Synthesis of Classical, Four-Carbon Bridged 5-Substituted Furo[2,3-d]pyrimidine and 6-Substituted Pyrrolo[2,3-d]pyrimidine Analogues as Antifolates

  摘要：

  We report, for the first time, the biological activities of four-carbon-atom bridged classical antifolates on dihydrofolate reductase (DHFR), thymidylate synthase (TS), and folylpolyglutamate synthetase (FPGS) as well as antitumor activity. Extension of the bridge homologation studies of classical two-carbon bridged antifolates, a 5-substituted 2,4-diaminofuro[2,3d]pyrimidine (1) and a 6-subsituted 2-amino-4-oxopyrrolo[2,3-d]pyrimidine (2), afforded two four-carbon bridged antifolates, analogues 5 and 6, with enhanced FPGS substrate activity and inhibitory activity against tumor cells in culture (EC50 <= 10(-7) M) compared with the two-carbon bridged analogues. These results support our original hypothesis that the distance and orientation of the side chain p-aminobenzoyl-L-glutamate moiety with respect to the pyrimidine ring are a crucial determinant of biological activity. In addition, this study demonstrates that, for classical antifolates that are substrates for FPGS, poor inhibitory activity against isolated target enzymes is not necessarily a predictor of a lack of antitumor activity.

  DOI：

  10.1021/jm058213s
• 作为产物：
  描述：

  Methyl 4-(5-chloro-5-oxopentyl)benzoate 在 sodium hydroxide 作用下， 以 甲醇 、 乙醚 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 78.5h， 生成 4-[4-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-6-yl)butyl]benzoic acid
  参考文献：
  名称：

  Synthesis of Classical, Four-Carbon Bridged 5-Substituted Furo[2,3-d]pyrimidine and 6-Substituted Pyrrolo[2,3-d]pyrimidine Analogues as Antifolates

  摘要：

  We report, for the first time, the biological activities of four-carbon-atom bridged classical antifolates on dihydrofolate reductase (DHFR), thymidylate synthase (TS), and folylpolyglutamate synthetase (FPGS) as well as antitumor activity. Extension of the bridge homologation studies of classical two-carbon bridged antifolates, a 5-substituted 2,4-diaminofuro[2,3d]pyrimidine (1) and a 6-subsituted 2-amino-4-oxopyrrolo[2,3-d]pyrimidine (2), afforded two four-carbon bridged antifolates, analogues 5 and 6, with enhanced FPGS substrate activity and inhibitory activity against tumor cells in culture (EC50 <= 10(-7) M) compared with the two-carbon bridged analogues. These results support our original hypothesis that the distance and orientation of the side chain p-aminobenzoyl-L-glutamate moiety with respect to the pyrimidine ring are a crucial determinant of biological activity. In addition, this study demonstrates that, for classical antifolates that are substrates for FPGS, poor inhibitory activity against isolated target enzymes is not necessarily a predictor of a lack of antitumor activity.

  DOI：

  10.1021/jm058213s

文献信息

• Synthesis and Discovery of High Affinity Folate Receptor-Specific Glycinamide Ribonucleotide Formyltransferase Inhibitors with Antitumor Activity
  作者：Yijun Deng、Yiqiang Wang、Christina Cherian、Zhanjun Hou、Steven A. Buck、Larry H. Matherly、Aleem Gangjee

  DOI：10.1021/jm8003366

  日期：2008.8.1

  diethyl-L-glutamate, and saponification afforded 2-5. Compounds 2-5 had negligible substrate activity for RFC but showed variably potent (nanomolar) and selective inhibitory activities toward Chinese hamster ovary cells that expressed FRalpha or FRbeta and toward FRalpha-expressing KB and IGROV1 human tumor cells. Inhibition of KB cell colony formation was also observed. Glycinamide ribonucleotide formyl transferase

  6-取代的经典吡咯并[2,3-d]嘧啶抗叶酸剂在杂环和苯甲酰-L-谷氨酸（分别为化合物2-5）之间具有三至六碳桥，由4-甲酰苯甲酸甲酯和与适当的三苯基溴化鏻的 Wittig 反应，然后还原并转化为 α-溴甲基酮。2,4-二氨基-4-氧代嘧啶与α-溴酮的环缩合、与L-谷氨酸二乙酯的偶联和皂化得到2-5。化合物 2-5 对 RFC 的底物活性可忽略不计，但对表达 FRalpha 或 FRbeta 的中国仓鼠卵巢细胞以及表达 FRalpha 的 KB 和 IGROV1 人类肿瘤细胞显示出不同的强效（纳摩尔）和选择性抑制活性。还观察到对KB细胞集落形成的抑制。甘氨酰胺核糖核苷酸甲酰转移酶 (GARFTase) 被鉴定为吡咯并 [2,3-d] 嘧啶的主要细胞内靶标。选择性 FR 靶向、缺乏 RFC 转运和 GARFTase 抑制导致有效抗肿瘤活性的综合特性是前所未有的，并保证将这些类似物开发为抗肿瘤剂。
• Discovery of novel tumor-targeted near-infrared probes with 6-substituted pyrrolo[2,3-d]pyrimidines as targeting ligands
  作者：Yining Zhang、Zijun Luo、Lixiao Guo、Haofeng Zhang、Tongdan Su、Zhenzhen Tan、Qian Ren、Can Zhang、Yan Fu、Ruijuan Xing、Ran Guo、Xiaowei Shi、Huicai Guo、Yi Liu、Lei Wang

  DOI：10.1016/j.ejmech.2023.115914

  日期：2023.12

  fluorescent probes were designed and synthesized based on previously reported 6-substituted pyrrolo[2,3-d]pyrimidine antifolates. All newly synthesized probes showed specific FR binding in vitro, whereas GT-NIR-4 and GT-NIR-5 with a benzene and a thiophene ring, respectively, on the side chain of pyrrolo[2,3-d]pyrimidine exhibited better FR binding affinity than that of GT-NIR-6 with folic acid as targeting

  由于叶酸受体 （FRs） 在某些类型的癌症中过表达，因此已经开发了多种用于肿瘤检测的 FR 靶向荧光探针。然而，报道的探针几乎都具有相同的叶酸靶向配体，具有不同的荧光团和/或接头。在本研究中，基于先前报道的 6-取代吡咯并[2,3-d] 嘧啶抗叶酸酯设计并合成了一系列新型肿瘤靶向近红外 （NIR） 分子荧光探针。所有新合成的探针在体外均显示出特异性 FR 结合，而吡咯并[2,3-d]嘧啶侧链上分别带有苯和噻吩环的 GT-NIR-4 和 GT-NIR-5 表现出比以叶酸为靶向配体的 GT-NIR-6 更好的 FR 结合亲和力。GT-NIR-4 在 KB 荷瘤小鼠中也显示出高肿瘤摄取，具有良好的药代动力学特性和生物安全性。这项工作展示了用抗叶酸代替叶酸作为肿瘤靶向 NIR 探针的靶向配体的首次尝试。