N'-<4--N-methylamino>benzoyl>-L-glutamic acid γ-hydrazide | 79640-75-8

• 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: N'-<4--N-methylamino>benzoyl>-L-glutamic acid γ-hydrazide
• 英文别名: 2-{4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoylamino}-4-hydrazinocarbonyl-(S)-butyric acid；methotrexate γ-hydrazide；methotrexate hydrazide；(2S)-2-[[4-[(2,4-diaminopteridin-6-yl)methyl-methylamino]benzoyl]amino]-5-hydrazinyl-5-oxopentanoic acid
• CAS: 79640-75-8
• 化学式: C₂₀H₂₄N₁₀O₄
• 分子量: 468.475
• InChiKey: YWIUAQJLEJPDSU-ZDUSSCGKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -5.1
• 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：
  228
• 氢给体数：
  6
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  N'-<4--N-methylamino>benzoyl>-L-glutamic acid γ-hydrazide 在 盐酸 、 亚硝酸特丁酯 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 (S)-4-Azidocarbonyl-2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-butyric acid
  参考文献：
  名称：

  Synthesis of methotrexate-antibody conjugates by regiospecific coupling and assessment of drug and antitumor activities

  摘要：

  In order to increase the retention of drug activity, regiospecific coupling has been used to synthesize conjugates of methotrexate (MTX, 1) with normal rabbit IgG (NRG) and a mouse anti-human renal cancer monoclonal IgG (Dal K-20). MTX gamma-methyl ester (4) was produced either by selective esterification of MTX or by coupling of 4-amino-4-deoxy-N10-methylpteroic acid (2) with suitable glutamic acid derivatives. The MTX gamma-methyl ester (4) was then converted to the corresponding hydrazide 6. An amide-linked conjugate was formed when the MTX gamma-hydrazide (6) was converted to reactive acylating species 7 by using tert-butyl nitrite or trifluoroacetaldehyde, which were reacted with nucleophilic centers, presumably epsilon-amino groups, in native IgG. A hydrazone-linked conjugate was formed when MTX gamma-hydrazide (6) was reacted directly with IgG that had first been oxidized with periodate to form polyaldehyde IgG. The regiospecifically synthesized conjugates were somewhat more effective inhibitors in vitro of dihydrofolate reductase and of colony formation by human renal cancer (Caki-1) cells than were control nonregiospecific conjugates.

  DOI：

  10.1021/jm00131a003
• 作为产物：
  描述：

  甲氨蝶呤 在 四氟硼酸-二乙醚络合物 一水合肼 、 sodium sulfate 作用下， 以 甲醇 为溶剂， 反应 68.0h， 生成 N'-<4--N-methylamino>benzoyl>-L-glutamic acid γ-hydrazide
  参考文献：
  名称：

  Synthesis of methotrexate-antibody conjugates by regiospecific coupling and assessment of drug and antitumor activities

  摘要：

  In order to increase the retention of drug activity, regiospecific coupling has been used to synthesize conjugates of methotrexate (MTX, 1) with normal rabbit IgG (NRG) and a mouse anti-human renal cancer monoclonal IgG (Dal K-20). MTX gamma-methyl ester (4) was produced either by selective esterification of MTX or by coupling of 4-amino-4-deoxy-N10-methylpteroic acid (2) with suitable glutamic acid derivatives. The MTX gamma-methyl ester (4) was then converted to the corresponding hydrazide 6. An amide-linked conjugate was formed when the MTX gamma-hydrazide (6) was converted to reactive acylating species 7 by using tert-butyl nitrite or trifluoroacetaldehyde, which were reacted with nucleophilic centers, presumably epsilon-amino groups, in native IgG. A hydrazone-linked conjugate was formed when MTX gamma-hydrazide (6) was reacted directly with IgG that had first been oxidized with periodate to form polyaldehyde IgG. The regiospecifically synthesized conjugates were somewhat more effective inhibitors in vitro of dihydrofolate reductase and of colony formation by human renal cancer (Caki-1) cells than were control nonregiospecific conjugates.

  DOI：

  10.1021/jm00131a003

文献信息

• Small molecule transcriptional activation domains
  申请人：Mapp K. Anna

  公开号：US20070105151A1

  公开（公告）日：2007-05-10

  The present invention relates to gene regulation. In particular, the present invention provides small molecule activation domain compositions and methods of making the same. The present invention further provides methods of regulating gene expression using the novel activation domains. The invention also provides methods of screening small molecule/compound libraries for identifying ligands of a protein or molecule of interest.

  本发明涉及基因调控。具体而言，本发明提供小分子激活域组合物及其制备方法。本发明还提供利用新型激活域调控基因表达的方法。本发明还提供筛选小分子/化合物库以鉴定感兴趣的蛋白质或分子配体的方法。
• Stereochemical Promiscuity in Artificial Transcriptional Activators
  作者：Sara J. Buhrlage、Brian B. Brennan、Aaron R. Minter、Anna K. Mapp

  DOI：10.1021/ja0536567

  日期：2005.9.1

  Small molecule replacements of transcriptional activation domains are highly desirable targets due to their utility as mechanistic tools and their long-term therapeutic potential for a variety of human diseases. Here, we examine the ability of amphipathic isoxazolidines differing only in the placement of constituent side chains to function as transcriptional activation domains. The results reveal that precise positioning of functional groups within a conformationally constrained small molecule scaffold is not required for transcription function; rather, the balance of polarity and hydrophobicity within the scaffold is the more important determinant of transcription function. This suggests that a number of different organic molecule scaffolds should function as transcriptional activator domains when appropriately functionalized, a hypothesis currently under investigation.
• Methotrexate analogs. 14. Synthesis of new .gamma.-substituted derivatives as dihydrofolate reductase inhibitors and potential anticancer agents
  作者：Andre Rosowsky、Ronald Forsch、Jack Uren、Michael Wick

  DOI：10.1021/jm00144a016

  日期：1981.12

  The gamma-tert-butyl ester (1), gamma-hydrazide (2), gamma-n-butylamide (3), and gamma-benzylamide (4) derivatives of methotrexate (MTX) were synthesized from 4-amino-4-deoxy-N10-methylpteroic acid (APA) and the appropriate blocked L-glutamic acid precursors with the aid of the peptide bond forming reagent diethyl phosphorocyanidate. The affinity of these side chain modified products for dihydrofolate reductase (DHFR) from Lactobacillus casei and L1210 mouse leukemic cells was determined spectrophotometrically or by competitive radioligand binding assay, and their cytotoxicity was evaluated against L1210 leukemic cells in culture. The results provide continuing support for the view that the "gamma-terminal region" of the MTX side chain is an attractive site for molecular modification of this anticancer agent.
• A Small Molecule Transcriptional Activation Domain
  作者：Aaron R. Minter、Brian B. Brennan、Anna K. Mapp

  DOI：10.1021/ja0473889

  日期：2004.9.1

  Artificial transcriptional activators are excellent tools for studying the mechanistic details of transcriptional regulation. Furthermore, as the correlation between a wide range of human diseases and misregulated transcription becomes increasingly evident, such molecules may in the long run serve as the basis for transcription-based therapeutic agents. The greatest challenge in this arena has been the discovery of organic molecules that are functional mimics of transcriptional activation domains, sequences of natural proteins that participate in a variety of protein-protein interactions to control transcriptional levels. We describe the first examples of small molecules that function in this capacity, isoxazolidines containing an array of polar and hydrophobic functional groups. Despite their small size, the most potent of the structures functions nearly as well as a natural activation domain.
• KRALOVEC, J.;SPENCER, G.;BLAIR, A. H.;MAMMEN, M.;SINGH, M.;GHOSE, T., J. MED. CHEM., 32,(1989) N1, C. 2426-2431
  作者：KRALOVEC, J.、SPENCER, G.、BLAIR, A. H.、MAMMEN, M.、SINGH, M.、GHOSE, T.

  DOI：——

  日期：——