2-desamino-5,8-dideazaisofolic acid | 118895-95-7

• 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-5,8-dideazaisofolic acid
• 英文别名: (2S)-2-[[4-[[(4-oxo-3H-quinazolin-6-yl)amino]methyl]benzoyl]amino]pentanedioic acid
• CAS: 118895-95-7
• 化学式: C₂₁H₂₀N₄O₆
• 分子量: 424.413
• InChiKey: DRAKYKMPCLOQIC-KRWDZBQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  31
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  157
• 氢给体数：
  5
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  聚合甲醛 、 2-desamino-5,8-dideazaisofolic acid 在 sodium cyanoborohydride 、 溶剂黄146 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 以59.2%的产率得到2-desamino-9-methyl-5,8-dideazaisofolic acid
  参考文献：
  名称：

  Studies on the antitumor effects of analogues of 5,8-dideazaisofolic acid and 5,8-dideazaisoaminopterin

  摘要：

  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.

  DOI：

  10.1016/0006-2952(95)00203-c
• 作为产物：
  描述：

  5-硝基靛红酸酐 在 palladium on activated charcoal 、 镍 氢气 、 三氟乙酸 作用下， 以 乙二醇甲醚 、 溶剂黄146 为溶剂， 反应 7.0h， 生成 2-desamino-5,8-dideazaisofolic acid
  参考文献：
  名称：

  Comparison of the biological effects of selected 5,8-dideazafolate analogs with their 2-desamino counterparts

  摘要：

  Three new 5,8-dideaza analogues of folic acid devoid of an amino group at position 2 have been prepared by using synthetic routes patterned after earlier methodologies. They were 2-desamino-5,8-dideazaisofolic acid, 2b, 2-desamino-10-thia-5,8-dideazafolic acid, 2c, and 2-desamino-10-oxa-5,8-dideazafolic acid, 2d. These compounds were found to be 4-6-fold more cytoxic toward L1210 leukemia cells than their 2-NH2 counterparts and to be poor inhibitors of mammalian thymidylate synthase. However, they were only 1.5-3-fold less inhibitory toward dihydrofolate reductase than the analogous compounds containing a 2-NH2 group. The known thymidylate synthase inhibitors 2-desamino-10-propargyl-5,8-dideazafolic acid and 10-propargyl-5,8-dideazafolic acid were included in this study for purposes of comparison.

  DOI：

  10.1021/jm00124a019

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.
• Comparison of the biological effects of selected 5,8-dideazafolate analogs with their 2-desamino counterparts
  作者：John B. Hynes、Shirish A. Patil、Robert L. Hagan、Aimee Cole、William Kohler、James H. Freisheim

  DOI：10.1021/jm00124a019

  日期：1989.4

  Three new 5,8-dideaza analogues of folic acid devoid of an amino group at position 2 have been prepared by using synthetic routes patterned after earlier methodologies. They were 2-desamino-5,8-dideazaisofolic acid, 2b, 2-desamino-10-thia-5,8-dideazafolic acid, 2c, and 2-desamino-10-oxa-5,8-dideazafolic acid, 2d. These compounds were found to be 4-6-fold more cytoxic toward L1210 leukemia cells than their 2-NH2 counterparts and to be poor inhibitors of mammalian thymidylate synthase. However, they were only 1.5-3-fold less inhibitory toward dihydrofolate reductase than the analogous compounds containing a 2-NH2 group. The known thymidylate synthase inhibitors 2-desamino-10-propargyl-5,8-dideazafolic acid and 10-propargyl-5,8-dideazafolic acid were included in this study for purposes of comparison.