4-[(2,4-Diamino-7-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-6-ylmethyl)-amino]-benzoic acid | 213256-80-5

• 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: 4-[(2,4-Diamino-7-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-6-ylmethyl)-amino]-benzoic acid
• 英文别名: 4-[(2,4-diamino-7-oxo-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-6-yl)methylamino]benzoic acid
• CAS: 213256-80-5
• 化学式: C₁₅H₁₆N₆O₃
• 分子量: 328.33
• InChiKey: HMJDMMBMQBFYEC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  156
• 氢给体数：
  5
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  4-[(2,4-Diamino-7-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-6-ylmethyl)-amino]-benzoic acid 在 sodium hydroxide 、 三乙胺 、 氰基膦酸 作用下， 反应 24.0h， 生成 (S)-2-{4-[(2,4-Diamino-7-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-6-ylmethyl)-amino]-benzoylamino}-pentanedioic acid
  参考文献：
  名称：

  Synthesis and Biological Activity of 4-Amino-7-oxo-Substituted Analogues of 5-Deaza-5,6,7,8-tetrahydrofolic Acid and 5,10-Dideaza-5,6,7,8-tetrahydrofolic Acid

  摘要：

  The 4-amino-7-oxo-substituted analogues of 5-deaza-5,6,7,8-tetrahydrofolic acid (5-DATHF) and 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF) were synthesized as potential antifolates. Treatment of the alpha,beta-unsaturated esters 11a-c, obtained in one synthetic step from commercially available para-substituted methyl benzoates (9a-c) and methyl 2-(bromomethyl)acrylate (10), with malononitrile in NaOMe/MeOH afforded the corresponding pyridones 12a-c. Formation of the pyrido[2,3-d]pyrimidines 13a-c was accomplished upon treatment of 12a-c with guanidine in methanol. After the hydrolysis of the ester group present in 13a-c, the resulting carboxylic acids 14a-c were treated with diethyl cyanophosphonate in Et3N/ DMF and coupled with L-glutamic acid dimethyl ester to give 15a-c. Finally, the basic hydrolysis of 15a-c yielded the desired 4-amino-7-oxo-substituted analogues 16a-c in 20-27% overall yield. Compounds 16a-c were tested in vitro against CCRF-CEM leukemia cells. The results obtained indicated that our 4-amino-7-oxo analogues are completely devoid of any activity, the IC50 being higher than 20 mu g/mL for all cases except 14c for which a value of 6.7 mu g/mL was obtained. These results seem to indicate that 16a-c are inactive precisely due to the presence of the carbonyl group in position C7, the distinctive feature or our synthetic methodology.

  DOI：

  10.1021/jm9801298
• 作为产物：
  描述：

  dimethyl 2-cyano-4-(4-methoxycarbonylphenylaminomethyl)pentanedioate 在 sodium hydroxide 作用下， 以 甲醇 为溶剂， 生成 4-[(2,4-Diamino-7-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-6-ylmethyl)-amino]-benzoic acid
  参考文献：
  名称：

  Synthesis and Biological Activity of 7-Oxo Substituted Analogues of 5-Deaza-5,6,7,8-tetrahydrofolic Acid (5-DATHF) and 5,10-Dideaza-5,6,7,8-tetrahydrofolic Acid (DDATHF)

  摘要：

  We recently described the syntheses of 12a-c, 4-amino-7-oxo substituted analogues of 5-deaza-5,6,7,8-tetrahydrofolic acid (5-DATHF), and 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF), in six steps from commercially available p-substituted methyl benzoates in: 20-27% overall yields; Such analogues were tested in vitro against CCRF-CEM leukemia cells and showed that they are completely devoid of any activity, the IC50 being higher than 20 mug/mL for all cases. To clarify if the presence of the carbonyl group in position C7, the distinctive feature of our synthetic. methodology, is the reason for this lack of activity, we have now obtained the 7-oxo substituted analogues of 5-DATHF and DDATHF, 18a-c, in 10-30% overall yield. Testing of 18a-c in vitro against CCRF-CEM leukemia cells revealed that these compounds are totally inactive. A molecular modeling study of 18b inside the active site of the complex El coli GARTFase-5-DATHF-GAR pointed to an electronic repulsion between the atoms of the 7-ore group and the carbonyl group of Arg90 as a possible explanation for the inactivity of 18a-c.

  DOI：

  10.1021/jm990411u

文献信息

• Selective Reduction of the 7-Oxo Group in Pyrido[2,3-d]pyrimidine-4,7-diones: A New Synthetic Approach to 5,10-Dideazatetrahydrofolic Acid (DDATHF)
  作者：José I. Borrell、Jordi Teixidó、Josep Lluís Matallana、Blanca Martínez-Teipel、Esther Couceiro

  DOI：10.3987/com-99-s129

  日期：——
• Synthesis and Biological Activity of 4-Amino-7-oxo-Substituted Analogues of 5-Deaza-5,6,7,8-tetrahydrofolic Acid and 5,10-Dideaza-5,6,7,8-tetrahydrofolic Acid
  作者：José I. Borrell、Jordi Teixidó、Blanca Martínez-Teipel、Josep Lluís Matallana、M. Teresa Copete、Ana Llimargas、Eva García

  DOI：10.1021/jm9801298

  日期：1998.8.1

  The 4-amino-7-oxo-substituted analogues of 5-deaza-5,6,7,8-tetrahydrofolic acid (5-DATHF) and 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF) were synthesized as potential antifolates. Treatment of the alpha,beta-unsaturated esters 11a-c, obtained in one synthetic step from commercially available para-substituted methyl benzoates (9a-c) and methyl 2-(bromomethyl)acrylate (10), with malononitrile in NaOMe/MeOH afforded the corresponding pyridones 12a-c. Formation of the pyrido[2,3-d]pyrimidines 13a-c was accomplished upon treatment of 12a-c with guanidine in methanol. After the hydrolysis of the ester group present in 13a-c, the resulting carboxylic acids 14a-c were treated with diethyl cyanophosphonate in Et3N/ DMF and coupled with L-glutamic acid dimethyl ester to give 15a-c. Finally, the basic hydrolysis of 15a-c yielded the desired 4-amino-7-oxo-substituted analogues 16a-c in 20-27% overall yield. Compounds 16a-c were tested in vitro against CCRF-CEM leukemia cells. The results obtained indicated that our 4-amino-7-oxo analogues are completely devoid of any activity, the IC50 being higher than 20 mu g/mL for all cases except 14c for which a value of 6.7 mu g/mL was obtained. These results seem to indicate that 16a-c are inactive precisely due to the presence of the carbonyl group in position C7, the distinctive feature or our synthetic methodology.
• Synthesis and Biological Activity of 7-Oxo Substituted Analogues of 5-Deaza-5,6,7,8-tetrahydrofolic Acid (5-DATHF) and 5,10-Dideaza-5,6,7,8-tetrahydrofolic Acid (DDATHF)
  作者：José I. Borrell、Jordi Teixidó、Josep Lluís Matallana、Blanca Martínez-Teipel、Carles Colominas、Marta Costa、Merche Balcells、Elisabeth Schuler、María José Castillo

  DOI：10.1021/jm990411u

  日期：2001.7.1

  We recently described the syntheses of 12a-c, 4-amino-7-oxo substituted analogues of 5-deaza-5,6,7,8-tetrahydrofolic acid (5-DATHF), and 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF), in six steps from commercially available p-substituted methyl benzoates in: 20-27% overall yields; Such analogues were tested in vitro against CCRF-CEM leukemia cells and showed that they are completely devoid of any activity, the IC50 being higher than 20 mug/mL for all cases. To clarify if the presence of the carbonyl group in position C7, the distinctive feature of our synthetic. methodology, is the reason for this lack of activity, we have now obtained the 7-oxo substituted analogues of 5-DATHF and DDATHF, 18a-c, in 10-30% overall yield. Testing of 18a-c in vitro against CCRF-CEM leukemia cells revealed that these compounds are totally inactive. A molecular modeling study of 18b inside the active site of the complex El coli GARTFase-5-DATHF-GAR pointed to an electronic repulsion between the atoms of the 7-ore group and the carbonyl group of Arg90 as a possible explanation for the inactivity of 18a-c.