methotrexate γ-tert-butyl ester | 79640-76-9

• 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: methotrexate γ-tert-butyl ester
• 英文别名: γ-tert-butyl N-(4-amino-4-deoxy-N¹⁰-methylpteroyl)-L-glutamate；(S)-5-(tert-butoxy)-2-(4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzamido)-5-oxopentanoic acid；SAR006-060；(2S)-2-[[4-[(2,4-diaminopteridin-6-yl)methyl-methylamino]benzoyl]amino]-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoic acid
• CAS: 79640-76-9
• 化学式: C₂₄H₃₀N₈O₅
• 分子量: 510.553
• InChiKey: AHTGHRYUTABCAE-INIZCTEOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.5
• 重原子数：
  37
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  200
• 氢给体数：
  4
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  methotrexate γ-tert-butyl ester 、 L-丙氨酸叔丁酯 生成 tert-butyl (4S)-4-[[4-[(2,4-diaminopteridin-6-yl)methyl-methylamino]benzoyl]amino]-5-[[(2S)-1-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]amino]-5-oxopentanoate
  参考文献：
  名称：

  KUEFNER, ULRIKE;LOHRMANN, UTE;MONTEJANO, YOLANDA D.;VITOLS, KARIN S.;HUEN+, BIOCHEMISTRY, 28,(1989) N, C. 2288-2297

  摘要：

  DOI：
• 作为产物：
  描述：

  4-[N-(2,4-二氨基-6-蝶啶甲基)-N-甲氨基]苯甲酸半盐酸盐n水 在 barium dihydroxide 、 氰基磷酸二乙酯 、 三乙胺 作用下， 反应 94.5h， 生成 methotrexate γ-tert-butyl ester
  参考文献：
  名称：

  Methotrexate Analogues. 25. Chemical and Biological Studies on the γ-tert-Butyl Esters of Methotrexate and Aminopterin

  摘要：

  gamma-tert-Butylaminopterin (gamma-tBAMT), the first example of an aminopterin (AMT) gamma-monoester, was synthesized, and new routes to the known N10-methyl analogue gamma-tert-butyl methotrexate (gamma-tBMTX) were developed. The inhibitory effects of gamma-tBAMT on the activity of purified dihydrofolate reductase (DHFR) from L1210 murine leukemia cells, the growth of L1210 cells and CEM human leukemic lymphoblasts in suspension culture, and the growth of several lines of human squamous cell carcinoma of the head and neck in monolayer culture were compared with the effects of gamma-tBMTX and the parent acids AMT and methotrexate (MTX). Patterns of cross-resistance to gamma-tBAMT, gamma-tBMTX, and AMT among several MTX-resistant cell lines were examined. In vivo antitumor activities of gamma-tBAMT and gamma-tBMTX were compared in mice with L1210 leukemia. While the activity of gamma-tBAMT was very close to that of gamma-tBMTX in the DHFR inhibition assay, the AMT ester was more potent than the MTX ester against cells in culture and against L1210 leukemia in vivo. Only partial cross-resistance was shown against gamma-tBMTX and gamma-tBAMT in cultured cells that were resistant to MTX by virtue of a transport defect or a combination of defective transport and elevated DHFR activity.

  DOI：

  10.1021/jm50001a021

文献信息

• [EN] METHOTREXATE ANALOGS AND METHODS OF USE<br/>[FR] ANALOGUES DE MÉTHOTREXATE ET PROCÉDÉS D'UTILISATION
  申请人：US HEALTH

  公开号：WO2021262693A1

  公开（公告）日：2021-12-30

  Compounds having general formula (I) or a pharmaceutically acceptable salt, N-oxide, or hydrate thereof are provided herein. Also provided are methods of making the compounds and methods of their use, including in treatment of cancer, autoimmune disorders, and viral infections.

  本文提供了具有通式（I）或其药用可接受的盐、N-氧化物或水合物的化合物。还提供了制备这些化合物的方法以及它们的使用方法，包括在癌症、自身免疫性疾病和病毒感染的治疗中的应用。
• 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.
• KUEFNER, ULRIKE;LOHRMANN, UTE;MONTEJANO, YOLANDA D.;VITOLS, KARIN S.;HUEN+, BIOCHEMISTRY, 28,(1989) N, C. 2288-2297
  作者：KUEFNER, ULRIKE、LOHRMANN, UTE、MONTEJANO, YOLANDA D.、VITOLS, KARIN S.、HUEN+

  DOI：——

  日期：——
• Methotrexate Analogues. 25. Chemical and Biological Studies on the γ-tert-Butyl Esters of Methotrexate and Aminopterin
  作者：Andre Rosowsky、James H. Freisheim、Henry Bader、Ronald A. Forsch、Sandra S. Susten、Carol A. Cucchi、Emil Frie

  DOI：10.1021/jm50001a021

  日期：1985.5

  gamma-tert-Butylaminopterin (gamma-tBAMT), the first example of an aminopterin (AMT) gamma-monoester, was synthesized, and new routes to the known N10-methyl analogue gamma-tert-butyl methotrexate (gamma-tBMTX) were developed. The inhibitory effects of gamma-tBAMT on the activity of purified dihydrofolate reductase (DHFR) from L1210 murine leukemia cells, the growth of L1210 cells and CEM human leukemic lymphoblasts in suspension culture, and the growth of several lines of human squamous cell carcinoma of the head and neck in monolayer culture were compared with the effects of gamma-tBMTX and the parent acids AMT and methotrexate (MTX). Patterns of cross-resistance to gamma-tBAMT, gamma-tBMTX, and AMT among several MTX-resistant cell lines were examined. In vivo antitumor activities of gamma-tBAMT and gamma-tBMTX were compared in mice with L1210 leukemia. While the activity of gamma-tBAMT was very close to that of gamma-tBMTX in the DHFR inhibition assay, the AMT ester was more potent than the MTX ester against cells in culture and against L1210 leukemia in vivo. Only partial cross-resistance was shown against gamma-tBMTX and gamma-tBAMT in cultured cells that were resistant to MTX by virtue of a transport defect or a combination of defective transport and elevated DHFR activity.