4-amino-4-deoxy-10-deazapteroyltriglutamate | 105099-94-3

• 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-10-deazapteroyltriglutamate
• CAS: 105099-94-3
• 化学式: C₃₀H₃₅N₉O₁₁
• 分子量: 697.662
• InChiKey: KBMQMURSXRRBAQ-FHWLQOOXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.88
• 重原子数：
  50.0
• 可旋转键数：
  19.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  340.1
• 氢给体数：
  9.0
• 氢受体数：
  13.0

反应信息

• 作为产物：
  描述：

  1-叔丁基 L-谷氨酸 在 哌啶 、 N-甲基吗啉 、 盐酸 、 4-二甲氨基吡啶 、 KH polyamide resin 、 sodium carbonate 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 38.25h， 生成 4-amino-4-deoxy-10-deazapteroyltriglutamate
  参考文献：
  名称：

  Folate analogs. 33. Synthesis of folate and antifolate poly-.gamma.-glutamates by [(9-fluorenylmethoxy)oxy]carbonyl chemistry and biological evaluation of certain methotrexate polyglutamate polylysine conjugates as inhibitors of the growth of H35 hepatoma cells

  摘要：

  Representative examples of folate and antifolate poly-gamma-glutamyl metabolites were synthesized via the [(9-fluorenylmethoxy)oxy]carbonyl (Fmoc) chemistry using the KH polyamide resin. Polyglutamate yields were consistently better in all cases compared to the previous Merrifield method, and the crude products were obtained in greater than 85% purity. The symmetrical anhydride (7) derived from alpha-tert-butyl N-Fmoc-L-glutamate (6) was used for the initial coupling of the first glutamate residue to the KH resin and also for subsequent chain elongation. The alpha-tert-butyl protective groups were not labile under the conditions used for the cleavage of the finished peptide from the resin. A series of poly-gamma-glutamyl metabolites of methotrexate (MTX) with a chain length ranging from two to five glutamyl residues were synthesized and coupled with poly(L-lysine) having an average molecular weight of 27,000 and 52,000. Each conjugate was tested for its ability to inhibit the growth of wild type (H35) and MTX transport resistant (H35R) strains of hepatoma cells in culture, the latter having a 100-fold reduced sensitivity to MTX. 4-Amino-4-deoxy-N10-methylpteroylglutamyl-gamma-glutamylpoly (L-lysine) conjugate [MTX(G2)-poly-L-Lys-52000] and MTX(G4)-poly-L-Lys-52000 were among the most active (I50 = 8.0 and 10 nM against H35 cells) MTX-polylysines synthesized to date, and they were somewhat more inhibitory to the transport resistant cells. MTX(G5)-poly-L-Lys-52000 was approximately 1000 times more effective than MTX(G5)-poly-D-Lys-52000 in inhibiting the growth of H35R hepatoma cells in culture, indicating that internal cleavage of the gamma-glutamate chain of the conjugate with subsequent release of MTX or shorter chain polyglutamates of MTX is unlikely to be an important determinant of MTX-polyglutamate polylysine cytotoxicity. The results indicate that MTX-polyglutamate poly(L-lysine) conjugates are taken up by the cells independently of MTX and probably via endocytosis.

  DOI：

  10.1021/jm00164a038

文献信息

• Synthesis and biological evaluation of poly-.gamma.-glutamyl metabolites of 10-deazaaminopterin and 10-ethyl-10-deazaaminopterin
  作者：M. G. Nair、N. T. Nanavati、P. Kumar、Y. Gaumont、R. L. Kisliuk

  DOI：10.1021/jm00396a029

  日期：1988.1

  The chemical synthesis of a series of poly-gamma-glutamyl metabolites of the experimental anticancer drugs 10-deazaaminopterin (10-DAAM) and 10-ethyl-10-deazaaminopterin (10-EDAAM) has been carried out by the solid-phase procedure. The synthetic products were identical with the poly-gamma-glutamyl metabolites of radiolabeled 10-DAAM and 10-EDAAM produced by normal mouse tissues with regard to elution

  实验性抗癌药物10-脱氮杂min蝶呤（10-DAAM）和10-乙基-10-脱氮杂min蝶呤（10-EDAAM）的一系列聚-γ-谷氨酰基代谢物的化学合成已通过固相程序进行。合成产物与正常小鼠组织产生的放射性标记的10-DAAM和10-EDAAM的聚-γ-谷氨酰胺代谢物在[（二乙氨基）乙基]纤维素柱上的洗脱体积以及人血浆叶酰聚谷氨酸水解酶的水解敏感性有关。 。在组织中检测到谷氨酸链长度最多为四个谷氨酸残基的聚-γ-谷氨酰基代谢物。用甲氨蝶呤（MTX）敏感和耐MTX的干酪乳杆菌和粪链球菌菌株评估抗叶酸活性。一般来说，抑制力随Glu链长度的增加而降低。但是，有两个例外。在10-DAAM中添加一个Glu残基可增强其对耐MTX干酪乳杆菌的效力，在10-EDAAM中添加一个Glu残基可增强对MTX敏感性干酪乳杆菌的效力。如先前对于MTX聚谷氨酸盐所示，聚谷氨酰化极大地增强了10-DAAM和10-EDAA