SYNTHESIS AND BIOLOGICAL-ACTIVITY OF OPEN-CHAIN ANALOGS OF 5,6,7,8-TETRAHYDROFOLIC ACID POTENTIAL ANTITUMOR AGENTS
SYNTHESIS AND BIOLOGICAL-ACTIVITY OF OPEN-CHAIN ANALOGS OF 5,6,7,8-TETRAHYDROFOLIC ACID POTENTIAL ANTITUMOR AGENTS
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DOI：
10.1021/jm00086a008
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发表时间：
1992-04-17
影响因子：
7.3
通讯作者：
FERONE, R
中科院分区：
文献类型：
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作者：
BIGHAM, EC;HODSON, SJ;FERONE, R
本研究描述了N-[4-[[3-（2,4-二氨基-1,6-二氢-6-氧-5-嘧啶基）丙基]氨基]苯甲酰- l-谷氨酸（5-DACTHF）类似物的嘌呤新生生物合成抑制剂的合成及其体外抗肿瘤活性。以受保护的嘧啶基丙醛和取代的苯甲酰谷氨酸为原料，通过关键的还原胺化步骤合成了苯环取代类似物。以对氨基苯甲酸或类似物为原料，逐步合成嘧啶和连接链取代类似物。这些化合物被测试为甲氨蝶呤摄取的抑制剂，作为与减少的叶酸运输系统结合的测量，作为甘氨酸酰胺核糖核苷酸转化酶的抑制剂，作为叶酸聚谷氨酸合成酶的底物，以及作为细胞培养中肿瘤细胞生长的抑制剂。除2′-F取代基外，环取代类似物的活性均低于母体化合物。用碳、硫或氧代替10-氮在体外产生的生物活性变化小于2倍。四原子连接链和嘧啶环上2位的氨基对于良好的活性是重要的。
This study describes the synthesis and in vitro antitumor activity of inhibitors of purine de novo biosynthesis that are analogues of N-[4-[[3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propyl]amino]benzoyl-L-glutamic acid (5-DACTHF). Benzene ring substituted analogues were synthesized from a protected pyrimidinyl propionaldehyde and a substituted benzoyl glutamate moiety by a key reductive amination step. Pyrimidine and linking chain substituted analogues were built up stepwise from p-aminobenzoic acid or analogues. The compounds were tested as inhibitors of methotrexate uptake as a measure of binding to the reduced folate transport system, as inhibitors of glycinamide ribonucleotide transformylase, as substrates for folylpolyglutamate synthetase, and as inhibitors of tumor cell growth in cell culture. With the exception of 2'-F substituent, the ring-substituted analogues are less active than the parent compound. Replacement of the 10-nitrogen by carbon, sulfur, or oxygen produced less than 2-fold changes to biological activity in vitro. A four-atom linking chain and an amino group at the 2-position on the pyrimidine ring are important for good activity.