diethyl 2-(S)-[5-methylamino-2,3-dihydro-1-oxo-2(1H)-isoindolyl]glutarate | 139988-46-8

• 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: diethyl 2-(S)-[5-methylamino-2,3-dihydro-1-oxo-2(1H)-isoindolyl]glutarate
• 英文别名: diethyl (S)-2-(5-(methylamino)-1-oxo-2-isoindolinyl)glutarate；diethyl (S)-2-[5-(methylamino)-1-oxo-2-isoindolinyl]glutarate；diethyl (2S)-2-[6-(methylamino)-3-oxo-1H-isoindol-2-yl]pentanedioate
• CAS: 139988-46-8
• 化学式: C₁₈H₂₄N₂O₅
• 分子量: 348.399
• InChiKey: GJSWUDZFAUEVEP-HNNXBMFYSA-N

物化性质

• 沸点：
  524.3±50.0 °C(Predicted)
• 密度：
  1.228±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  25
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  84.9
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  diethyl 2-(S)-[5-methylamino-2,3-dihydro-1-oxo-2(1H)-isoindolyl]glutarate 在 sodium hydroxide 、 碳酸氢钠 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 (S)-2-(5-(((1,2-dihydro-3-methyl-1-oxobenzo-quinazolin-9-yl)methyl)methylamino)-1-oxo-2-isoindolinyl)glutaric acid
  参考文献：
  名称：

  Benzo[f]quinazoline Inhibitors of Thymidylate Synthase: Methyleneamino-Linked Aroylglutamate Derivatives

  摘要：

  Syntheses of several new inhibitors of thymidylate synthase (TS) structurally related to folic acid are described in which the pterin portion of the folate molecule is replaced by a benzo[f]quinazoline moiety, but which retain the natural methyleneamino link to the benzoylglutamate side chain. The effect on enzyme activity and cytotoxicity of various changes in the structure of the (p-aminobenzoyl)glutamate side chain are reported. Replacement of the benzamide portion of the (p-aminobenzoyl)glutamate moiety with 2-fluorobenzamido, 2-isoindolinyl, 1,2-benzisothiazol-2-yl, and 2-thenamido moieties varied in effect from a 9-fold diminution of TS activity to a 5-fold enhancement, while cytotoxic potency on SW-480 and MCF-7 tumor lines showed increases ranging from 3.6-to 450-fold. The detrimental effect on enzyme activity and cytotoxicity of alkyl substitution on the PABA nitrogen is confirmed for these compounds, in contrast with several series of previously reported quinazoline antifolates (2). Substitution of a C3-methyl substituent for 3-amino had little effect on TS activity but was beneficial in terms of solubility and cytotoxicity. The excellent combination of TS inhibitory activity, FPGS substrate activity, and affinity for the reduced folate transport system in the most potent of these derivatives, 3e, resulted in IC50 values of 0.2-0.8 nM against these tumor lines.

  DOI：

  10.1021/jm00032a019
• 作为产物：
  描述：

  4-溴-2-甲基苯甲酸 在 tris-(dibenzylideneacetone)dipalladium(0) 、 palladium on activated charcoal 吡啶 、 sodium hydroxide 、 N-溴代丁二酰亚胺(NBS) 、 氯化亚砜 、 三叔丁基膦 、 氢气 、 十六烷基三甲基溴化铵 、 potassium carbonate 、 过氧化苯甲酰 作用下， 以 甲醇 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 20.0~90.0 ℃ 、303.98 kPa 条件下， 反应 326.0h， 生成 diethyl 2-(S)-[5-methylamino-2,3-dihydro-1-oxo-2(1H)-isoindolyl]glutarate
  参考文献：
  名称：

  Synthesis and in Vitro Antifolate Activity of Rotationally Restricted Aminopterin and Methotrexate Analogues

  摘要：

  Heretofore unknown analogues of aminopterin (AMT) and methotrexate (MTX) in which free rotation of the amide bond between the phenyl ring and amino acid side chain is prevented by a CH2 bridge were synthesized and tested for in vitro antifolate activity. The K-i of the AMT analogue (9) against human dihydrofolate reductase (DHFR) was 34 pM, whereas that of the MTX analogue (10) was 2100 pM. Both compounds were less potent than the parent drugs. However, although the difference between AMT and MTX was < 2-fold, the difference between 9 and 10 was 62-fold, suggesting that the effect of N-10-methyl substitution is amplified in the bridged compounds. The K-i values of 9 and 10 as inhibitors of [H-3]MTX influx into CCRF-CEM human leukemia cells via the reduced folate carrier (RFC) were 0.28 and 1.1 muM, respectively. The corresponding K-i and K-t values determined earlier for AMT and MTX were 5.4 and 4.7 muM, respectively. Thus, in contrast to its unfavorable effect on DHFR binding, the CH2 bridge increased RFC binding. In a 72 h growth assay with CCRF-CEM cells, the IC50 valuess of 9 and 10 were 5.1 and 140 nM, respectively, a 27-fold difference that was qualitatively consistent with the observed combination of weaker DHFR binding and stronger RFC binding. Although rotationally restricted inhibitors of other enzymes of folate pathway enzymes have been described previously, 9 and 10 are the first reported examples of DHFR inhibitors of this type.

  DOI：

  10.1021/jm040122s

文献信息

• Pharmaceutical compounds
  申请人：Burroughs Wellcome Co.

  公开号：US05405851A1

  公开（公告）日：1995-04-11

  The present invention relates to novel benzoquinazoline thymidylate synthase inhibitors, to pharmaceutical formulations containing them and to their use in medicine.

  本发明涉及新型苯并喹唑嘧啶酸甲脱氧胸苷合成酶抑制剂，以及含有它们的药物配方和它们在医学上的应用。
• Pharmaceutically active benzoquinazoline compounds
  申请人：THE WELLCOME FOUNDATION LIMITED

  公开号：EP1199307B1

  公开（公告）日：2004-02-25
• US6306865B1
  申请人：——

  公开号：US6306865B1

  公开（公告）日：2001-10-23
• [EN] NOVEL 8-CARBONYL CHROMAN DERIVATIVES, PREPARATION AND THERAPEUTIC USE THEREOF<br/>[FR] NOUVEAUX DERIVES 8-CARBONYL CHROMANES, LEUR PREPARATION ET LEUR UTILISATION EN THERAPEUTIQUE
  申请人：AVENTIS PHARMA SA

  公开号：WO2001009125A1

  公开（公告）日：2001-02-08

  La présente invention concerne de nouveaux dérivés 8-carbonyl chromanes qui inhibent la farnésyle transférase. La présente invention concerne également leur préparation et leur utilisation en thérapeutique.