Synthesis and biological evaluation of poly-gamma-glutamyl metabolites of 10-deazaaminopterin and 10-ethyl-10-deazaaminopterin.
Synthesis and biological evaluation of poly-gamma-glutamyl metabolites of 10-deazaaminopterin and 10-ethyl-10-deazaaminopterin.
复制标题
10-脱氮氨基蝶呤和10-乙基-10-脱氮氨基蝶呤的聚-γ-谷氨酰代谢物的合成和生物学评价。
DOI：
10.1021/jm00396a029
复制
发表时间：
1988
影响因子：
7.3
通讯作者：
Kisliuk,RL
中科院分区：
文献类型：
--
作者：
Nair,MG;Nanavati,NT;Kumar,P;Gaumont,Y;Kisliuk,RL
图1.在正常哺乳动物组织中形成的天然代谢物，并评价其抗叶酸活性。作为旨在开发抗叶酸药物的持续计划的一部分，22本文详细介绍了10-DAAM和10-EDAAM的聚-7-谷氨酰代谢物的化学合成和抗叶酸活性的评价。化学10-DAAM（1）和10-EDAAM（2），在谷氨酸部分均匀地用14 C标记，如所述合成。从梅里菲尔德氯甲基肽树脂和叔-Boc-L-谷氨酸-苄酯（3）开始，制备一系列具有不同谷氨酸酯链长的树脂结合的叔-Boc-L-谷氨酰基-7-（L-谷氨酰基）n-7-L-谷氨酰基-α-苄酯（4）。12 4-氨基-4-脱氧-10-脱氮杂蝶酸（5）和4-氨基-4-脱氧-10-乙基-10-脱氮杂蝶酸（6）的制备方法在本实验室以前开发过。16蝶酸5和6通过用异丁酸异丁酯处理转化为它们相应的混合胺7和8（图1）。
Figure 1. natural metabolites formed in normal mammalian tissues and to evaluate their antifolate activities. As part of a continuing program aimed at the development of antifolate drugs, 22 this paper details the chemical synthesis and evaluation of antifolate activity ofthe poly-7-glutamyl metabolites of 10-DAAM and 10-EDAAM.Chemistry 10-DAAM (1) and 10-EDAAM (2), labeled uniformly with 14C at the glutamate moiety, were synthesized as described. 23 Starting from Merrifield chloromethyl pep-tide resin and ieri-Boc-L-glutamic acid-benzyl ester (3), a series of resin-bound iert-Boc-L-glutamyl-7-(L-glutamyl)„-7-L-glutamyl-a-benzyl esters (4) with varying glutamate chain lengths were prepared. 12 4-Amino-4-deoxy-10-deazapteroic acid (5) and4-amino-4-deoxy-10-ethyl-10-deazapteroic acid (6) were prepared by procedures previously developed in this laboratory. 16 Pteroic acids 5 and 6 were converted to their corresponding mixed an-hydrides 7 an 8 (Figure 1) by treatment with isobutyl