2-desamino-2-methyl-N¹⁰-propargyl-5,8-dideazaisohomopteroic acid | 133933-35-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 2-desamino-2-methyl-N¹⁰-propargyl-5,8-dideazaisohomopteroic acid
• 英文别名: 4-[[(2-methyl-4-oxo-1H-quinazolin-6-yl)methyl-prop-2-ynylamino]methyl]benzoic acid
• CAS: 133933-35-4
• 化学式: C₂₁H₁₉N₃O₃
• 分子量: 361.4
• InChiKey: DUWGHFDCUXMZET-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.57
• 重原子数：
  27.0
• 可旋转键数：
  6.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  86.29
• 氢给体数：
  2.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  2-desamino-2-methyl-N¹⁰-propargyl-5,8-dideazaisohomopteroic acid 在 吡啶 、 sodium hydroxide 、 N,N'-二环己基碳二亚胺 作用下， 以 乙腈 为溶剂， 反应 83.0h， 生成 2-desamino-2-methyl-N¹⁰-propargyl-5,8-dideazahomofolic acid
  参考文献：
  名称：

  Folate analogs. 35. Synthesis and biological evaluation of 1-deaza, 3-deaza, and bridge-elongated analogs of N10-propargyl-5,8-dideazafolic acid

  摘要：

  Structural modifications at the pyrimidine ring and at the C-9,N-10-bridge region of the thymidylate synthase (TS) inhibitors N-10-propargyl-5,8-dideazafolate (1; PDDF; CB 3717), 2-desamino-N10-propargyl-5,8-dideazafolate (2, DPDDF), and 2-desamino-2-methyl-N-10-propargyl-5,8-dideazafolate (3, DMPDDF) have been carried out. Methods for the synthesis of 2-desamino-N-10-propargyl-1,5,8-trideazafolate (4), 2-desamino-2-methyl-N-10-propargyl-3,5,8-trideazafolate (5a), and 2-desamino-2-methyl-N10-propargyl-5,8-dideaza-1,2-dihydrofolate (6) have been developed. The bridge-extended analogues isohomo-PDDF (7) and isohomo-DMPDDF (8) contain an additional methylene group interposed between N-10 and the phenyl ring of 1 and 3, respectively. All new compounds were evaluated as inhibitors of TS and the growth of tumor cells in culture. Selected analogues were tested as substrates of folylpolyglutamate synthetase (FPGS) and striking differences in substrate activity were observed among these compounds, indicating that structural modifications at the pyrimidine ring of classical antifolates profoundly influence their polyglutamylation. Enzyme inhibition data established that both N1 and N3-H of the pyrimidine ring are essential for efficient binding of quinazoline-type antifolates to human TS.

  DOI：

  10.1021/jm00113a011
• 作为产物：
  描述：

  4-{[(丙-2-炔-1-基)胺]甲基}苯甲酸甲酯 在 sodium hydroxide 、 magnesium oxide 作用下， 以 N,N-二甲基乙酰胺 、 乙腈 为溶剂， 反应 36.0h， 生成 2-desamino-2-methyl-N¹⁰-propargyl-5,8-dideazaisohomopteroic acid
  参考文献：
  名称：

  Folate analogs. 35. Synthesis and biological evaluation of 1-deaza, 3-deaza, and bridge-elongated analogs of N10-propargyl-5,8-dideazafolic acid

  摘要：

  Structural modifications at the pyrimidine ring and at the C-9,N-10-bridge region of the thymidylate synthase (TS) inhibitors N-10-propargyl-5,8-dideazafolate (1; PDDF; CB 3717), 2-desamino-N10-propargyl-5,8-dideazafolate (2, DPDDF), and 2-desamino-2-methyl-N-10-propargyl-5,8-dideazafolate (3, DMPDDF) have been carried out. Methods for the synthesis of 2-desamino-N-10-propargyl-1,5,8-trideazafolate (4), 2-desamino-2-methyl-N-10-propargyl-3,5,8-trideazafolate (5a), and 2-desamino-2-methyl-N10-propargyl-5,8-dideaza-1,2-dihydrofolate (6) have been developed. The bridge-extended analogues isohomo-PDDF (7) and isohomo-DMPDDF (8) contain an additional methylene group interposed between N-10 and the phenyl ring of 1 and 3, respectively. All new compounds were evaluated as inhibitors of TS and the growth of tumor cells in culture. Selected analogues were tested as substrates of folylpolyglutamate synthetase (FPGS) and striking differences in substrate activity were observed among these compounds, indicating that structural modifications at the pyrimidine ring of classical antifolates profoundly influence their polyglutamylation. Enzyme inhibition data established that both N1 and N3-H of the pyrimidine ring are essential for efficient binding of quinazoline-type antifolates to human TS.

  DOI：

  10.1021/jm00113a011