4-amino-4-deoxy-N¹⁰-methylpteroyl-L-glutamic γ-monohydroxamic acid | 77410-31-2

• 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: 4-amino-4-deoxy-N¹⁰-methylpteroyl-L-glutamic γ-monohydroxamic acid
• 英文别名: Methotrexate gamma-hydroxamic acid；(2S)-2-[[4-[(2,4-diaminopteridin-6-yl)methyl-methylamino]benzoyl]amino]-5-(hydroxyamino)-5-oxopentanoic acid
• CAS: 77410-31-2
• 化学式: C₂₀H₂₃N₉O₅
• 分子量: 469.46
• InChiKey: YUQBNZUBNMWBAQ-ZDUSSCGKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.6
• 重原子数：
  34
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  223
• 氢给体数：
  6
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  甲氨蝶呤 在 N-甲基吗啉 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 羟胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以62%的产率得到4-amino-4-deoxy-N¹⁰-methylpteroyl-L-glutamic γ-monohydroxamic acid
  参考文献：
  名称：

  Methotrexate γ-hydroxamate derivatives as potential dual target antitumor drugs

  摘要：

  A series of new aminopteroyl-based hydroxamate derivatives were synthesized and tested in vitro in cell culture models as potential dual target drugs. These compounds were designed to target two families of enzymes, matrix metalloproteinases (MMP) and a folate enzyme, dihydrofolate reductase (DHFR). These enzymes are the components of two unrelated cellular pathways and they are often over-expressed in metastasizing tumors. In addition to the synthesis and full structural characterization of the hybrid molecules, we describe their inhibitory activities against a series of MMPs (MMP-2, MMP-7, MMP-9, MMP-14) and DHFR, as well as their antiproliferative activity in three cancer cell lines. The new hydroxamate derivatives of MTX proved to be effective inhibitors of MMPs and DHFR in the micromolar and nanomolar range, respectively. Furthermore, they showed strong antiproliferative activity against A549 cells (non-small cell lung carcinoma), and PPC-1 and Tsu-Pr1 prostate cancer cell lines. Therefore, based on the present results, these bi-functional drugs may be good candidates to target specific tumors in animal models due to potential combined effects on two pathways crucial for tumor development. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2006.11.017

文献信息

• Methotrexate analogs. 13. Chemical and pharmacological studies on amide, hydrazide, and hydroxamic acid derivatives of the glutamate side chain
  作者：Andre Rosowsky、Cheng-Sein Yu、Jack Uren、Herbert Lazarus、Michael Wick

  DOI：10.1021/jm00137a016

  日期：1981.5

  thylpteroic acid (APA) with several alkyl, aralkyl, and aryl amines, in the presence or absence of N-hydroxysuccinimide, was employed in order to prepare new lipid-soluble bis(amide) derivatives of methotrexate (MTX) as potential prodrugs. MTX dianilide was likewise prepared, in comparable yield, from APA and L-glutamic acid dianilide via the mixed carboxylic--carbonic anhydride method. Dihydrazide

  在存在或不存在N-羟基琥珀酰亚胺的情况下，使用碳二亚胺介导的4-氨基-4-脱氧-N10-甲基蝶酸（APA）与几种烷基，芳烷基和芳基胺的缩合反应以制备新的脂溶性甲氨蝶呤（MTX）的双（酰胺）衍生物作为潜在的前药。同样地，APA和L-谷氨酸二苯胺通过羧酸-碳酸酐混合法以相似的产率制备了MTX二苯胺。MTX的二酰肼和双（N-甲基酰肼）衍生物很容易由MTX二乙酯形成。然而，与羟胺的反应产生了MTXγ-单异羟肟酸作为唯一的分离产物。双加合物似乎形成了，但在后处理过程中不稳定。通过由APA和L-谷氨酸的γ-单异羟肟酸酯的独立混合酸酐合成来确认产物的身份。用N，N-二甲基肼处理MTX二甲基酯出乎意料地产生了MTXγ-单甲基酯。MTX二苯胺对小鼠的L1210白血病具有活性，按q3d X 3时间表在10％Tween 80中腹膜内给予160 mg / kg的剂量，可使寿命延长+ 155％。双（对氯苄基酰胺），
• Methotrexate γ-hydroxamate derivatives as potential dual target antitumor drugs
  作者：M. Amélia Santos、Eva A. Enyedy、Elisa Nuti、Armando Rossello、Natalia I. Krupenko、Sergey A. Krupenko

  DOI：10.1016/j.bmc.2006.11.017

  日期：2007.2.1

  A series of new aminopteroyl-based hydroxamate derivatives were synthesized and tested in vitro in cell culture models as potential dual target drugs. These compounds were designed to target two families of enzymes, matrix metalloproteinases (MMP) and a folate enzyme, dihydrofolate reductase (DHFR). These enzymes are the components of two unrelated cellular pathways and they are often over-expressed in metastasizing tumors. In addition to the synthesis and full structural characterization of the hybrid molecules, we describe their inhibitory activities against a series of MMPs (MMP-2, MMP-7, MMP-9, MMP-14) and DHFR, as well as their antiproliferative activity in three cancer cell lines. The new hydroxamate derivatives of MTX proved to be effective inhibitors of MMPs and DHFR in the micromolar and nanomolar range, respectively. Furthermore, they showed strong antiproliferative activity against A549 cells (non-small cell lung carcinoma), and PPC-1 and Tsu-Pr1 prostate cancer cell lines. Therefore, based on the present results, these bi-functional drugs may be good candidates to target specific tumors in animal models due to potential combined effects on two pathways crucial for tumor development. (c) 2006 Elsevier Ltd. All rights reserved.