2-desamino-2,9-dimethyl-5,8-dideazaisofolic acid | 133446-46-5

• 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: 2-desamino-2,9-dimethyl-5,8-dideazaisofolic acid
• 英文别名: 2-(4-{[Methyl-(2-methyl-4-oxo-3,4-dihydro-quinazolin-6-yl)-amino]-methyl}-benzoylamino)-pentanedioic acid；(2S)-2-[[4-[[methyl-(2-methyl-4-oxo-3H-quinazolin-6-yl)amino]methyl]benzoyl]amino]pentanedioic acid
• CAS: 133446-46-5
• 化学式: C₂₃H₂₄N₄O₆
• 分子量: 452.467
• InChiKey: ROWWLMPPVFHRBH-IBGZPJMESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  33
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  148
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  4-氯甲基苯甲酰氯 在 2,6-二甲基吡啶 、 sodium hydroxide 、 calcium carbonate 作用下， 以 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 10.5h， 生成 2-desamino-2,9-dimethyl-5,8-dideazaisofolic acid
  参考文献：
  名称：

  喹唑啉抗叶酸胸苷酸合酶抑制剂：C2-甲基系列中的桥键修饰和构象受限的类似物。

  摘要：

  已经制备了几种基于C2-甲基喹唑啉的抗叶酸剂，其中C9，N10桥被反向的N9，C10单元代替。通过在N9和C10处引入其他取代基以及对对氨基苯甲酸酯环的修饰，对该系列进行了广泛的研究。还合成了含有亚甲基氧杂，亚甲基硫杂和硫杂桥单元的C 2-甲基喹唑啉类似物29、30和31。通常，亲本C 2-甲基-N 10-炔丙基喹唑啉抗叶酸2中桥单元的这些等排替代物作为分离的胸苷酸合酶（TS）抑制剂的效力要低得多，但几种至少与培养中的L1210细胞生长抑制剂一样有效。对氨基苯甲酸酯环与双环系统75和76的融合也降低了对TS的活性，但又产生了高度细胞毒性的化合物。

  DOI：

  10.1021/jm00111a042

文献信息

• Studies on the antitumor effects of analogues of 5,8-dideazaisofolic acid and 5,8-dideazaisoaminopterin
  作者：Robert L. Hagan、John B. Hynes、Meade Pimsler、Roy L. Kisliuk

  DOI：10.1016/0006-2952(95)00203-c

  日期：1995.9

  Six new analogues of 5,8-dideazaisofolic acid and 5,8-dideazaisoaminopterin were synthesized in an effort to obtain enhanced antitumor activity. The modifications included the replacement of the 2-amino group by hydrogen or methyl as well as the inclusion of a methyl substituent at position 9. Based upon activity against L1210 leukemia cells in culture, three of the new analogues together with one compound described previously were evaluated for cytotoxicity in vitro using three human tumor cell lines (Cole 320 DM, Hep G2 and HL-60). The most effective compound was 2-desamino-N-9-methyl-5,8-dideazaisoaminopterin (2c) with the HL-60 cells being the most sensitive to its cytotoxic effects. These analogues were evaluated in vitro as inhibitors of dihydrofolate reductase (DHFR) and thymidylate synthase (TS) from human as well as bacterial (Lactobacillus casei) sources. All four of the 4-amino analogues were most effective toward L. casei DHFR compared with human DHFR, with 2-desamino-2-methyl-5,8-dideazaisoaminopterin (2d) and its 9-methyl derivative (2e) having 818- and 430-fold greater selectivity (L. caseilhuman). Most of the compounds studied were found to be only modest inhibitors of human TS (I-50 values = 1.5 to 20 mu M) and were therefore at least 40-fold less inhibitory than 10-propargyl-5,8-dideazafolic acid. Nevertheless, reversal of cytotoxicity studies with thymidine, hypoxanthine and folinic acid using the HL-60 cell line suggested that TS is the primary target for these analogues.
• Quinazoline antifolate thymidylate synthase inhibitors: bridge modifications and conformationally restricted analogs in the C2-methyl series
  作者：Peter R. Marsham、Ann L. Jackman、Anthony J. Hayter、Melanie R. Daw、Jayne L. Snowden、Brigid M. O'Connor、Joel A. M. Bishop、A. Hilary Calvert、Leslie R. Hughes

  DOI：10.1021/jm00111a042

  日期：1991.7

  N10 bridge has been replaced by the reversed N9,C10 unit. This series was extensively studied by incorporating further substituents at N9 and C10 as well as by modifications to the p-aminobenzoate ring. The C2-methylquinazoline analogues 29, 30, and 31 containing the methyleneoxa, methylenethia, and thia bridge units were also synthesized. In general these isosteric replacements of the bridge unit

  已经制备了几种基于C2-甲基喹唑啉的抗叶酸剂，其中C9，N10桥被反向的N9，C10单元代替。通过在N9和C10处引入其他取代基以及对对氨基苯甲酸酯环的修饰，对该系列进行了广泛的研究。还合成了含有亚甲基氧杂，亚甲基硫杂和硫杂桥单元的C 2-甲基喹唑啉类似物29、30和31。通常，亲本C 2-甲基-N 10-炔丙基喹唑啉抗叶酸2中桥单元的这些等排替代物作为分离的胸苷酸合酶（TS）抑制剂的效力要低得多，但几种至少与培养中的L1210细胞生长抑制剂一样有效。对氨基苯甲酸酯环与双环系统75和76的融合也降低了对TS的活性，但又产生了高度细胞毒性的化合物。