4-[(2,4-Diaminopyrido[2,3-d]pyrimidin-6-yl)methyl-formylamino]benzoic acid | 132343-91-0

• 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: 4-[(2,4-Diaminopyrido[2,3-d]pyrimidin-6-yl)methyl-formylamino]benzoic acid
• CAS: 132343-91-0
• 化学式: C₁₆H₁₄N₆O₃
• 分子量: 338.326
• InChiKey: OKPFEWIRQFZPMM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  148
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  4-[(2,4-Diaminopyrido[2,3-d]pyrimidin-6-yl)methyl-formylamino]benzoic acid 在 sodium hydroxide 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.41h， 生成 N^α-<4-pyrimidin-6-yl)methyl>amino>benzoyl>-N^δ-hemiphthaloyl-L-ornithine
  参考文献：
  名称：

  Synthesis and Potent Antifolate Activity and Cytotoxicity of B-Ring Deaza Analogues of the Nonpolyglutamatable Dihydrofolate Reductase Inhibitor N^α-(4-Amino-4-deoxypteroyl)-N^δ-hemiphthaloyl-l-ornithine (PT523)

  摘要：

  Six new B-ring analogues of the nonpolyglutamatable antifolate N-alpha-(4-amino-4-deoxypteroyl)-N-delta-hemiphthaloyl-L-ornithine (PT523, 3) were synthesized with a view to determining the effect of modifications at the 5- and/or 8-position on dihydrofolate reductase (DHFR) binding and tumor cell growth inhibition The 5- and 8-deaza analogues were prepared from methyl 2-L-amino-5-phthalimidopentanoate and 4-amino-4-deoxy-N-10-formyl-5-deaza- and -8-deazapteroic acid, respectively. The 5,8-dideaza analogues were prepared from methyl 2-L-[(4-aminobenzoyl)-amino]-5-phthalimidopentanoate and 2,4-diaminoquinazoline-6-carbonitriles. The K-i for inhibition of human DHFR by the 5-deaza and 5-methyl-5-deaza analogues was about the same as that of 3 (0.35 pM), 11-fold lower than that of aminopterin (AMT, 1), and 15-fold lower than that of methotrexate (MTX, 2). However the K-i of the 8-deaza analogue was 27-fold lower than that of 1, and that of the 5,8-dideaza, 5-methyl-5,8-dideaza, and 5-chloro-5,8-dideaza analogues was approximately 50-fold lower. This trend was consistent with the published literature on the corresponding DHFR inhibitors with a glutamate side chain. In colony formation assays against the human head and neck squamous carcinoma cell line SCC25 after 72 h of treatment, the 5- and 8-deaza analogues were approximately as potent as 3, whereas the 5,8-dideaza analogue was 3 times more potent. 5-Methyl and 5-chloro substitution was also favorable, with the 5-methyl-5-deaza analogue being 2.5-fold more potent than the 5-deaza analogue. However the effect of 5-methyl substitution was less pronounced in the 5,8-dideaza analogues than in the 5-deaza analogues. The 5-chloro-5,8-dideaza analogue of 3 was the most active member of the series, with an IC50 = 0.33 nM versus 1.8 nM for 3 and 15 nM for MTX. The 5-methyl-5-deaza analogue of 3 was also tested at the National Cancer Institute against a panel of 50 human tumor cell lines in culture and was consistently more potent than 3, with IC50 values in the low nanomolar to subnanomolar range against most of the tumors. Leukemia and colorectal carcinoma cell lines were generally most sensitive, though good activity was also observed against CNS tumors and carcinomas of the breast and prostate. The results of this study demonstrate that B-ring analogues of 3 inhibit DHFR activity and tumor cell colony formation as well as, or better than, the parent compound. In view of the fact that 3 and its B-ring analogues cannot form polyglutamates, their high cytotoxicity relative to the corresponding B-ring analogues of AMT is noteworthy.

  DOI：

  10.1021/jm980477+
• 作为产物：
  描述：

  对氨基苯甲酸 在 镍 氢气 、 溶剂黄146 作用下， 75.0 ℃ 、303.98 kPa 条件下， 反应 20.0h， 生成 4-[(2,4-Diaminopyrido[2,3-d]pyrimidin-6-yl)methyl-formylamino]benzoic acid
  参考文献：
  名称：

  叶酸，氨基蝶呤和带有L-鸟氨酸侧链的甲氨蝶呤的新的deaza类似物的合成及其体外生物学活性。

  摘要：

  N alpha-pteroyl-L-鸟氨酸（Pter-Orn）的5-deaza和5,8-dideaza类似物，N alpha-（4-amino）的5-deaza，8-deaza和5,8-dideaza类似物合成了-4-脱氧蝶酰基-L-鸟氨酸（APA-Orn）和Nα-（4-氨基-4-脱氧-N10-甲基蝶酰基）-L-鸟氨酸（mAPA-Orn）的Nδ-羧甲基衍生物并作为二氢叶酸还原酶（DHFR）的抑制剂和培养物中肿瘤细胞生长的抑制剂进行了测试。用N-甲基-（4-氨基苯甲酰基）-N-δ-（苄氧羰基）-L-鸟氨酸甲酯对2-乙酰氨基-6-甲酰基吡啶并[2,3-d]嘧啶-4（3H）-进行还原胺化，然后除去封闭基团提供了Pter-Orn的5-deaza类似物，而甲基Nα-（4-氨基苯甲酰基）-Nδ-（苄氧基羰基）-L-鸟氨酸酯的N-烷基化与2-氨基-6-（溴甲基）喹唑啉-4（3H）-1，脱保护得到相应的5，8-dideaza类似物。2

  DOI：

  10.1021/jm00108a032

文献信息

• ROSOWSKY, ANDRE;FORSCH, RONALD A.;BADER, HENRY;FREISHEIM, JAMES H., J. MED. CHEM., 34,(1991) N, C. 1447-1454
  作者：ROSOWSKY, ANDRE、FORSCH, RONALD A.、BADER, HENRY、FREISHEIM, JAMES H.

  DOI：——

  日期：——
• Synthesis and Potent Antifolate Activity and Cytotoxicity of B-Ring Deaza Analogues of the Nonpolyglutamatable Dihydrofolate Reductase Inhibitor <i>N</i>^α-(4-Amino-4-deoxypteroyl)-<i>N</i>^δ-hemiphthaloyl-<scp>l</scp>-ornithine (PT523)
  作者：Andre Rosowsky、Joel E. Wright、Chitra M. Vaidya、Henry Bader、Ronald A. Forsch、Clara E. Mota、Jorge Pardo、Cindy S. Chen、Ying-Nan Chen

  DOI：10.1021/jm980477+

  日期：1998.12.1

  Six new B-ring analogues of the nonpolyglutamatable antifolate N-alpha-(4-amino-4-deoxypteroyl)-N-delta-hemiphthaloyl-L-ornithine (PT523, 3) were synthesized with a view to determining the effect of modifications at the 5- and/or 8-position on dihydrofolate reductase (DHFR) binding and tumor cell growth inhibition The 5- and 8-deaza analogues were prepared from methyl 2-L-amino-5-phthalimidopentanoate and 4-amino-4-deoxy-N-10-formyl-5-deaza- and -8-deazapteroic acid, respectively. The 5,8-dideaza analogues were prepared from methyl 2-L-[(4-aminobenzoyl)-amino]-5-phthalimidopentanoate and 2,4-diaminoquinazoline-6-carbonitriles. The K-i for inhibition of human DHFR by the 5-deaza and 5-methyl-5-deaza analogues was about the same as that of 3 (0.35 pM), 11-fold lower than that of aminopterin (AMT, 1), and 15-fold lower than that of methotrexate (MTX, 2). However the K-i of the 8-deaza analogue was 27-fold lower than that of 1, and that of the 5,8-dideaza, 5-methyl-5,8-dideaza, and 5-chloro-5,8-dideaza analogues was approximately 50-fold lower. This trend was consistent with the published literature on the corresponding DHFR inhibitors with a glutamate side chain. In colony formation assays against the human head and neck squamous carcinoma cell line SCC25 after 72 h of treatment, the 5- and 8-deaza analogues were approximately as potent as 3, whereas the 5,8-dideaza analogue was 3 times more potent. 5-Methyl and 5-chloro substitution was also favorable, with the 5-methyl-5-deaza analogue being 2.5-fold more potent than the 5-deaza analogue. However the effect of 5-methyl substitution was less pronounced in the 5,8-dideaza analogues than in the 5-deaza analogues. The 5-chloro-5,8-dideaza analogue of 3 was the most active member of the series, with an IC50 = 0.33 nM versus 1.8 nM for 3 and 15 nM for MTX. The 5-methyl-5-deaza analogue of 3 was also tested at the National Cancer Institute against a panel of 50 human tumor cell lines in culture and was consistently more potent than 3, with IC50 values in the low nanomolar to subnanomolar range against most of the tumors. Leukemia and colorectal carcinoma cell lines were generally most sensitive, though good activity was also observed against CNS tumors and carcinomas of the breast and prostate. The results of this study demonstrate that B-ring analogues of 3 inhibit DHFR activity and tumor cell colony formation as well as, or better than, the parent compound. In view of the fact that 3 and its B-ring analogues cannot form polyglutamates, their high cytotoxicity relative to the corresponding B-ring analogues of AMT is noteworthy.
• Synthesis and in vitro biological activity of new deaza analogs of folic acid, aminopterin, and methotrexate with an L-ornithine side chain
  作者：Andre Rosowsky、Ronald A. Forsch、Henry Bader、James H. Freisheim

  DOI：10.1021/jm00108a032

  日期：1991.4

  culture. Reductive amination of 2-acetamido-6-formylpyrido[2,3-d]pyrimidine-4(3H)-one with methyl N alpha-(4-aminobenzoyl)-N delta-(benzyloxycarbonyl)-L-ornithinate followed by removal of the blocking groups afforded the 5-deaza analogue of Pter-Orn, whereas N-alkylation of methyl N alpha-(4-aminobenzoyl)-N delta-(benzyloxycarbonyl)-L-ornithinate with 2-amino-6-(bromomethyl)quinazolin-4(3H)-one and deprotection

  N alpha-pteroyl-L-鸟氨酸（Pter-Orn）的5-deaza和5,8-dideaza类似物，N alpha-（4-amino）的5-deaza，8-deaza和5,8-dideaza类似物合成了-4-脱氧蝶酰基-L-鸟氨酸（APA-Orn）和Nα-（4-氨基-4-脱氧-N10-甲基蝶酰基）-L-鸟氨酸（mAPA-Orn）的Nδ-羧甲基衍生物并作为二氢叶酸还原酶（DHFR）的抑制剂和培养物中肿瘤细胞生长的抑制剂进行了测试。用N-甲基-（4-氨基苯甲酰基）-N-δ-（苄氧羰基）-L-鸟氨酸甲酯对2-乙酰氨基-6-甲酰基吡啶并[2,3-d]嘧啶-4（3H）-进行还原胺化，然后除去封闭基团提供了Pter-Orn的5-deaza类似物，而甲基Nα-（4-氨基苯甲酰基）-Nδ-（苄氧基羰基）-L-鸟氨酸酯的N-烷基化与2-氨基-6-（溴甲基）喹唑啉-4（3H）-1，脱保护得到相应的5，8-dideaza类似物。2