Improved synthetic routes to 5,8-dideazapteroylglutamates amenable to the formation of poly-gamma-L-glutamyl derivatives.
Improved synthetic routes to 5,8-dideazapteroylglutamates amenable to the formation of poly-gamma-L-glutamyl derivatives.
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改进的 5,8-二脱氮蝶酰谷氨酸合成路线可形成聚-γ-L-谷氨酰衍生物。
DOI：
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发表时间：
1983
影响因子：
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通讯作者：
M. B. Benjamin
中科院分区：
文献类型：
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作者：
J. Hynes;Y. C. Yang;G. McCue;M. B. Benjamin
叶酸的喹唑啉类似物(5，8-二氮杂环丁酸酯)作为潜在的抗肿瘤药物、生化探针和/或亲和配体被用于叶酸需要的酶的纯化。其中最主要的是5，8-二氮杂异戊酰谷氨酸酯，5，8-二氮杂异丙基谷氨酸(IAHQ)，一种已被证实在体外对人结肠腺癌细胞生长具有活性的化合物，以及10-甲酰基-5，8-二脱氮杂蝶酰谷氨酸，它是甘氨酰胺核苷酸转换酶的底物，也是哺乳动物胸苷合成酶的有效抑制物。用高效液相色谱(HPLC)测定这些化合物的纯度，开发了制备这些化合物的新方法。在每种情况下，L-谷氨酸的羧基都用叔丁酯基团保护，因为这些基团随后可以很容易地用三氟乙酸去除，而不需要最终产品的分解或消旋。这种方法已被证明在形成含有1-3个额外谷氨基残基的IAHQ的伽马-L-谷氨基衍生物方面具有特殊的价值。
A variety of quinazoline analogues of folic acid (5,8-dideazafolates) are of interest as potential antineoplastic agents, biochemical probes, and/or affinity ligands for the purification of folate requiring enzymes. Chief among these are 5,8-dideazaisopteroylglutamate, 5,8-dideazaisoPteGlu, (IAHQ), a compound with proven activity against the growth of human colon adenocarcinoma cells in vitro, and 10-formyl-5,8-dideazapteroylglutamic acid, which serves as a substrate for glycinamide ribonucleotide transformylase and is also an effective inhibitor of mammalian thymidylate synthase. New methods for preparing these compounds in excellent purity as determined by high performance liquid chromatography (HPLC) have been developed. In each case the carboxyl groups of L-glutamic acid are protected with t-butyl ester groups, since these can subsequently be removed readily using trifluoroacetic acid without decomposition or racemization of the final product. This approach has proven to be of particular value in the formation of gamma-L-glutamyl derivatives of IAHQ containing 1-3 additional glutamyl residues.