4-amino-4-deoxy-10-methyl-10-deazapteroic acid | 80576-76-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 蝶啶及其衍生物
• 英文名称: 4-amino-4-deoxy-10-methyl-10-deazapteroic acid
• 英文别名: 4-[1-(2,4-Diaminopteridin-6-yl)propan-2-yl]benzoic acid
• CAS: 80576-76-7
• 化学式: C₁₆H₁₆N₆O₂
• 分子量: 324.342
• InChiKey: RJWDMIZMPFWLPF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  141
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  4-amino-4-deoxy-10-methyl-10-deazapteroic acid 在 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 27.5h， 生成 methyl 2-L-[4-[2-(2,4-diaminopteridin-6-yl)propyl]benzoyl]amino-5-phthalimidopentanoate
  参考文献：
  名称：

  Analogues of the Potent Nonpolyglutamatable Antifolate N^α-(4-Amino-4-deoxypteroyl)-N^δ-hemiphthaloyl-l-ornithine (PT523) with Modifications in the Side Chain, p-Aminobenzoyl Moiety, or 9,10-Bridge:  Synthesis and in Vitro Antitumor Activity

  摘要：

  Seven N-alpha-(4-amino-4-deoxypteroyl)-N-sigma-hemiphtha (2, PT523) analogues were synthesized by modifications of the literature synthesis of the corresponding AMT (1) analogues and were tested as inhibitors of tumor cell growth. in growth assays against cultured CCRF-CEM human leukemic cells exposed to drug for 72 h, the IC50 values of analogues in which N-10 was replaced by CH2 and CHMe were found to be 0.55 +/- 0.07 and 0.63 +/- 0.08 nM, and thus these analogues are more potent than 1 (IC50 = 4.4 +/- 1.0 nM) or 2 (IC50 = 1.5 +/-: 0.39 nM). The 10-ethyl-10-deaza analogue of 2 (IC50 = 1.2 +/- 0.25 nM) was not statistically different from 2 but was more potent than edatrexate, the 10-ethyl-10-deaza analogue of 1, which had an IC50 of 3.3 +/- 0.36 nM. In contrast, the analogue of 2 with both an ethyl and a CO2Me group at the 10-position had an IC50 of 54 +/- 4.9 nM, showing this modification to be unfavorable. The 4-amino-1-naphthoic acid analogue of 2 had an IC50 Of 1.2 +/- 0.22 nM, indicating that replacement of the p-aminobenzoic acid (pABA) moiety does not diminish cytotoxicity. The analogues in which the (CH2)(3) Side chain was replaced by slightly longer CH2SCH2 and (CH2)(2)-SCH2 groups gave IC50 values of 4.4 +/- 1.1 and 5.0 +/- 0.56 nM and thus were somewhat less potent than the parent molecule. However the analogues in which the aromatic COOH group was at the meta and para positions of the phthaloyl ring had IC50 values of 7.5 +/- 0.47 and 55 +/- 0.07 nM, confirming the low potency we had previously observed with these compounds against other cell lines. Overall, the results in this study support the conclusion that, while the position of the phthaloyl COOH group and the length of the amino acid side chain in 2 are important determinants of cytotoxic potency, changes in the pABA region and 9,10-bridge are well-tolerated and can even increase potency.

  DOI：

  10.1021/jm990630f
• 作为产物：
  描述：

  对乙基苯甲酸 在 正丁基锂 、 potassium triiodide 、 二氧化碳 、 溴 、 二异丙胺 作用下， 生成 4-amino-4-deoxy-10-methyl-10-deazapteroic acid
  参考文献：
  名称：

  10-烷基-10-去氮杂蝶呤的合成和抗肿瘤活性。一种方便的10-脱氮蝶呤合成方法。

  摘要：

  大规模合成有效的抗肿瘤药10-脱氮蝶呤的要求导致了该化合物及其10-烷基类似物的简便合成的发展。用3-甲氧基烯丙基氯将适当的对烷基苯甲酸的二异丙基氨基锂锂生成的二价阴离子烷基化。在pH 7-8下将所得的4-（对羧基苯基）-1-甲氧基-1-丁烯溴化，得到2-溴-4-（对羧基苯基）丁醛。与2,4,5,6-四氨基嘧啶缩合，然后原位氧化所得的二蝶啶，得到结晶的10-烷基-10-脱氮基-4-氨基-4-脱氧蝶酸。通过混合酸酐法将蝶酸与谷氨酸二乙酯偶联，然后在室温下皂化，以得到目标10-脱氮蝶呤类化合物。10-烷基化合物作为叶酸依赖性细菌的生长抑制剂与10-脱氮蝶呤大致相等。它们抑制干酪乳杆菌和L1210衍生的二氢叶酸还原酶的能力也相似。体外转运特性提示10-烷基类似物的治疗指数得到改善。相对于小鼠中的L1210，在LD10剂量下，寿命延长百分比为+ 151％（甲氨蝶呤），+ 178％（10-脱氮蝶呤），+

  DOI：

  10.1021/jm00352a026

文献信息

• DEGRAW, J. I.;BROWN, V. H.;TAGAWA, H.;KISLIUK, R. L.;GAUMONT, Y.;SIROTNAK+, J. MED. CHEM., 1982, 25, N 10, 1227-1230
  作者：DEGRAW, J. I.、BROWN, V. H.、TAGAWA, H.、KISLIUK, R. L.、GAUMONT, Y.、SIROTNAK+

  DOI：——

  日期：——
• Synthesis and antitumor activity of 10-alkyl-10-deazaminopterins. A convenient synthesis of 10-deazaminopterin
  作者：J. I. DeGraw、V. H. Brown、H. Tagawa、R. L. Kisliuk、Y. Gaumont、F. M. Sirotnak

  DOI：10.1021/jm00352a026

  日期：1982.10

  Requirements for large-scale synthesis of the potent antitumor drug 10-deazaminopterin have led to development of a facile synthesis of this compound and its 10-alkyl analogues. The lithium diisopropyl amide generated dianions of appropriate p-alkylbenzoic acids were alkylated with 3-methoxyallyl chloride. The resulting 4-(p-carboxyphenyl)-1-methoxy-1-butenes were brominated at pH 7-8 to afford the

  大规模合成有效的抗肿瘤药10-脱氮蝶呤的要求导致了该化合物及其10-烷基类似物的简便合成的发展。用3-甲氧基烯丙基氯将适当的对烷基苯甲酸的二异丙基氨基锂锂生成的二价阴离子烷基化。在pH 7-8下将所得的4-（对羧基苯基）-1-甲氧基-1-丁烯溴化，得到2-溴-4-（对羧基苯基）丁醛。与2,4,5,6-四氨基嘧啶缩合，然后原位氧化所得的二蝶啶，得到结晶的10-烷基-10-脱氮基-4-氨基-4-脱氧蝶酸。通过混合酸酐法将蝶酸与谷氨酸二乙酯偶联，然后在室温下皂化，以得到目标10-脱氮蝶呤类化合物。10-烷基化合物作为叶酸依赖性细菌的生长抑制剂与10-脱氮蝶呤大致相等。它们抑制干酪乳杆菌和L1210衍生的二氢叶酸还原酶的能力也相似。体外转运特性提示10-烷基类似物的治疗指数得到改善。相对于小鼠中的L1210，在LD10剂量下，寿命延长百分比为+ 151％（甲氨蝶呤），+ 178％（10-脱氮蝶呤），+
• Analogues of the Potent Nonpolyglutamatable Antifolate <i>N</i>^α-(4-Amino-4-deoxypteroyl)-<i>N</i>^δ-hemiphthaloyl-<scp>l</scp>-ornithine (PT523) with Modifications in the Side Chain, <i>p</i>-Aminobenzoyl Moiety, or 9,10-Bridge:  Synthesis and in Vitro Antitumor Activity
  作者：Andre Rosowsky、Joel E. Wright、Chitra M. Vaidya、Ronald A. Forsch、Henry Bader

  DOI：10.1021/jm990630f

  日期：2000.4.1

  Seven N-alpha-(4-amino-4-deoxypteroyl)-N-sigma-hemiphtha (2, PT523) analogues were synthesized by modifications of the literature synthesis of the corresponding AMT (1) analogues and were tested as inhibitors of tumor cell growth. in growth assays against cultured CCRF-CEM human leukemic cells exposed to drug for 72 h, the IC50 values of analogues in which N-10 was replaced by CH2 and CHMe were found to be 0.55 +/- 0.07 and 0.63 +/- 0.08 nM, and thus these analogues are more potent than 1 (IC50 = 4.4 +/- 1.0 nM) or 2 (IC50 = 1.5 +/-: 0.39 nM). The 10-ethyl-10-deaza analogue of 2 (IC50 = 1.2 +/- 0.25 nM) was not statistically different from 2 but was more potent than edatrexate, the 10-ethyl-10-deaza analogue of 1, which had an IC50 of 3.3 +/- 0.36 nM. In contrast, the analogue of 2 with both an ethyl and a CO2Me group at the 10-position had an IC50 of 54 +/- 4.9 nM, showing this modification to be unfavorable. The 4-amino-1-naphthoic acid analogue of 2 had an IC50 Of 1.2 +/- 0.22 nM, indicating that replacement of the p-aminobenzoic acid (pABA) moiety does not diminish cytotoxicity. The analogues in which the (CH2)(3) Side chain was replaced by slightly longer CH2SCH2 and (CH2)(2)-SCH2 groups gave IC50 values of 4.4 +/- 1.1 and 5.0 +/- 0.56 nM and thus were somewhat less potent than the parent molecule. However the analogues in which the aromatic COOH group was at the meta and para positions of the phthaloyl ring had IC50 values of 7.5 +/- 0.47 and 55 +/- 0.07 nM, confirming the low potency we had previously observed with these compounds against other cell lines. Overall, the results in this study support the conclusion that, while the position of the phthaloyl COOH group and the length of the amino acid side chain in 2 are important determinants of cytotoxic potency, changes in the pABA region and 9,10-bridge are well-tolerated and can even increase potency.