Methyl 4-(5-chloro-5-oxopentyl)benzoate | 1026793-20-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: Methyl 4-(5-chloro-5-oxopentyl)benzoate
• CAS: 1026793-20-3
• 化学式: C₁₃H₁₅ClO₃
• 分子量: 254.713
• InChiKey: GGQRKZLBBCRLLG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  17
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  43.4
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  Methyl 4-(5-chloro-5-oxopentyl)benzoate 以 乙醚 、 N,N-二甲基甲酰胺 为溶剂， 反应 73.5h， 生成 methyl 4-[4-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-6-yl)butyl]benzoate
  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：

  (3-丙羧基)三苯基溴化膦 在 palladium on activated charcoal 草酰氯 、 氢气 、 sodium hydride 作用下， 以 四氢呋喃 、 二氯甲烷 、 氯仿 、 二甲基亚砜 、 乙酸乙酯 为溶剂， 20.0 ℃ 、344.74 kPa 条件下， 反应 7.5h， 生成 Methyl 4-(5-chloro-5-oxopentyl)benzoate
  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

• Cyclopenta[d]pyrimidines And Substituted Cyclopenta[d]pyrimidines As Antitubulin and Microtubule Targeting Agents, Monocyclic Pyrimidines As Tubulin Inhibitors, And Pyrrolopyrimidines As Targeted Antifolates And Tubulin and Multiple Receptor Tyrosine Kinase Inhibition And Antitumor Agents
  申请人：Duquesne University of the Holy Spirit

  公开号：US20160304525A1

  公开（公告）日：2016-10-20

  The present invention provides a compound of Formula I, and salts thereof, and a pharmaceutical composition comprising a compound of Formula I: wherein R 1 is selected from the group consisting of and R 2 is an alkyl group having from one to ten carbon atoms, or wherein R 2 is selected from the group consisting of R 1 is an alkyl group having from one to ten carbon atoms; and R is H, or an alkyl group having from one to ten carbon atoms, and R 3 is H, an alkyl group having from one to ten carbon atoms, or a halogen. Preferably the compound of Formula V includes wherein R 3 is a halogen, and most preferably wherein the halogen is chlorine. Methods of treating a patient with cancer with these compounds are also provided.

  本发明提供了一种化合物I的盐，以及包括化合物I的药物组合物：其中R1选自以下组成的群体，R2是具有一到十个碳原子的烷基基团，或者R2选自以下组成的群体，R1是具有一到十个碳原子的烷基基团；R是H，或者具有一到十个碳原子的烷基基团，R3是H，具有一到十个碳原子的烷基基团，或者卤素。优选化合物V包括其中R3是卤素，最优选其中卤素是氯。还提供了使用这些化合物治疗癌症患者的方法。
• 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。
• Synthesis of Classical, Four-Carbon Bridged 5-Substituted Furo[2,3-<i>d</i>]pyrimidine and 6-Substituted Pyrrolo[2,3-<i>d</i>]pyrimidine Analogues as Antifolates
  作者：Aleem Gangjee、Yibin Zeng、John J. McGuire、Roy L. Kisliuk

  DOI：10.1021/jm058213s

  日期：2005.8.1

  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.