(S)-diethyl 2-(4-(4-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo-[2,3-d]pyrimidin-5-yl)butyl)benzamido)pentanedioate | 1055042-91-5

• 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)-diethyl 2-(4-(4-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo-[2,3-d]pyrimidin-5-yl)butyl)benzamido)pentanedioate
• 英文别名: diethyl (2S)-2-[[4-[4-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)butyl]benzoyl]amino]pentanedioate
• CAS: 1055042-91-5
• 化学式: C₂₆H₃₃N₅O₆
• 分子量: 511.578
• InChiKey: KYMRHIYVKAETSD-IBGZPJMESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  37
• 可旋转键数：
  15
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  165
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (S)-diethyl 2-(4-(4-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo-[2,3-d]pyrimidin-5-yl)butyl)benzamido)pentanedioate 在 sodium hydroxide 作用下， 反应 2.0h， 以88%的产率得到(S)-2-(4-(4-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]-pyrimidin-5-yl)butyl)benzamido)pentanedioic acid
  参考文献：
  名称：

  Discovery of 5-Substituted Pyrrolo[2,3-d]pyrimidine Antifolates as Dual-Acting Inhibitors of Glycinamide Ribonucleotide Formyltransferase and 5-Aminoimidazole-4-carboxamide Ribonucleotide Formyltransferase in De Novo Purine Nucleotide Biosynthesis: Implications of Inhibiting 5-Aminoimidazole-4-carboxamide Ribonucleotide Formyltransferase to AMPK Activation and Antitumor Activity

  摘要：

  We synthesized 5-substituted pyrrolo[2,3-d]pyrimidine antifolates (compounds 5-10) with one-to-six bridge carbons and a benozyl ring in the side chain as antitumor agents. Compound 8 with a 4-carbon bridge was the most active analogue and potently inhibited proliferation of folate receptor (FR) alpha-expressing Chinese hamster ovary and KB human tumor cells. Growth inhibition was reversed completely or in part by excess folic acid, indicating that FR alpha is involved in cellular uptake, and resulted in S-phase accumulation and apoptosis. Antiproliferative effects of compound 8 toward KB cells were protected by excess adenosine but not thymidine, establishing de novo purine nucleotide biosynthesis as the targeted pathway. However, 5-aminoimidazole-4-carboxamide (AICA) protection was incomplete, suggesting inhibition of both AICA ribonucleotide formyltransferase (AICARFTase) and glycinamide ribonucleotide formyltransferase (GARFTase). Inhibition of GARFTase and AICARFTase by compound 8 was confirmed by cellular metabolic assays and resulted in ATP pool depletion. To our knowledge, this is the first example of an antifolate that acts as a dual inhibitor of GARFTase and AICARFTase as its principal mechanism of action.

  DOI：

  10.1021/jm401328u
• 作为产物：
  描述：

  ethyl 4-(6-oxohexyl)benzoate 在 N-甲基吗啉 、 盐酸 、 2-氯-4,6-二甲氧基-1,3,5-三嗪 、 5,5-二溴-2,2-二甲基-4,6-二酮-1,3-二氧杂环己烷 、 sodium acetate 、 sodium hydroxide 作用下， 以 甲醇 、 乙醚 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 57.0h， 生成 (S)-diethyl 2-(4-(4-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo-[2,3-d]pyrimidin-5-yl)butyl)benzamido)pentanedioate
  参考文献：
  名称：

  Discovery of 5-Substituted Pyrrolo[2,3-d]pyrimidine Antifolates as Dual-Acting Inhibitors of Glycinamide Ribonucleotide Formyltransferase and 5-Aminoimidazole-4-carboxamide Ribonucleotide Formyltransferase in De Novo Purine Nucleotide Biosynthesis: Implications of Inhibiting 5-Aminoimidazole-4-carboxamide Ribonucleotide Formyltransferase to AMPK Activation and Antitumor Activity

  摘要：

  We synthesized 5-substituted pyrrolo[2,3-d]pyrimidine antifolates (compounds 5-10) with one-to-six bridge carbons and a benozyl ring in the side chain as antitumor agents. Compound 8 with a 4-carbon bridge was the most active analogue and potently inhibited proliferation of folate receptor (FR) alpha-expressing Chinese hamster ovary and KB human tumor cells. Growth inhibition was reversed completely or in part by excess folic acid, indicating that FR alpha is involved in cellular uptake, and resulted in S-phase accumulation and apoptosis. Antiproliferative effects of compound 8 toward KB cells were protected by excess adenosine but not thymidine, establishing de novo purine nucleotide biosynthesis as the targeted pathway. However, 5-aminoimidazole-4-carboxamide (AICA) protection was incomplete, suggesting inhibition of both AICA ribonucleotide formyltransferase (AICARFTase) and glycinamide ribonucleotide formyltransferase (GARFTase). Inhibition of GARFTase and AICARFTase by compound 8 was confirmed by cellular metabolic assays and resulted in ATP pool depletion. To our knowledge, this is the first example of an antifolate that acts as a dual inhibitor of GARFTase and AICARFTase as its principal mechanism of action.

  DOI：

  10.1021/jm401328u

文献信息

• Discovery of 5-Substituted Pyrrolo[2,3-<i>d</i>]pyrimidine Antifolates as Dual-Acting Inhibitors of Glycinamide Ribonucleotide Formyltransferase and 5-Aminoimidazole-4-carboxamide Ribonucleotide Formyltransferase in De Novo Purine Nucleotide Biosynthesis: Implications of Inhibiting 5-Aminoimidazole-4-carboxamide Ribonucleotide Formyltransferase to AMPK Activation and Antitumor Activity
  作者：Shermaine Mitchell-Ryan、Yiqiang Wang、Sudhir Raghavan、Manasa Punaha Ravindra、Eric Hales、Steven Orr、Christina Cherian、Zhanjun Hou、Larry H. Matherly、Aleem Gangjee

  DOI：10.1021/jm401328u

  日期：2013.12.27

  We synthesized 5-substituted pyrrolo[2,3-d]pyrimidine antifolates (compounds 5-10) with one-to-six bridge carbons and a benozyl ring in the side chain as antitumor agents. Compound 8 with a 4-carbon bridge was the most active analogue and potently inhibited proliferation of folate receptor (FR) alpha-expressing Chinese hamster ovary and KB human tumor cells. Growth inhibition was reversed completely or in part by excess folic acid, indicating that FR alpha is involved in cellular uptake, and resulted in S-phase accumulation and apoptosis. Antiproliferative effects of compound 8 toward KB cells were protected by excess adenosine but not thymidine, establishing de novo purine nucleotide biosynthesis as the targeted pathway. However, 5-aminoimidazole-4-carboxamide (AICA) protection was incomplete, suggesting inhibition of both AICA ribonucleotide formyltransferase (AICARFTase) and glycinamide ribonucleotide formyltransferase (GARFTase). Inhibition of GARFTase and AICARFTase by compound 8 was confirmed by cellular metabolic assays and resulted in ATP pool depletion. To our knowledge, this is the first example of an antifolate that acts as a dual inhibitor of GARFTase and AICARFTase as its principal mechanism of action.