Gangjee Aleem, Lin Xin, Kisliuk Roy L, McGuire John J
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, USA.
J Med Chem. 2005 Nov 17;48(23):7215-22. doi: 10.1021/jm058234m.
Two novel classical antifolates N-{4-[(2,4-diamino-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid 3 and N-{4-[(2-amino-4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid 4 were designed, synthesized, and evaluated as antitumor agents. Compounds 3 and 4 were obtained from 2,4-diamino-5-methylpyrrolo[2,3-d]pyrimidine 7 and 2-amino-4-oxo-5-methylpyrrolo[2,3-d]pyrimidine 12, respectively, in a concise three-step sequence. Compound 3 is the first example, to our knowledge, of a 2,4-diamino classical antifolate that has potent inhibitory activity against both human dihydrofolate reductase (DHFR) and human thymidylate synthase (TS). Compound 4 was a dual DHFR-TS inhibitor against the bifunctional enzyme derived from Toxoplasma gondii (tg). Further evaluation of the mechanism of action of 3 implicated DHFR as its primary intracellular target. Both 3 and 4 were folylpolyglutamate synthetase (FPGS) substrates. Compound 3 also inhibited the growth of several human tumor cell lines in culture with GI50 < 10(-8) M. This study shows that the pyrrolo[2,3-d]pyrimidine scaffold is conducive to dual DHFR-TS and tumor inhibitory activity, and the potency is determined by the 4-position substituent.
设计、合成并评估了两种新型经典抗叶酸剂N-{4-[(2,4-二氨基-5-甲基-4,7-二氢-3H-吡咯并[2,3-d]嘧啶-6-基)硫代]苯甲酰}-L-谷氨酸3和N-{4-[(2-氨基-4-氧代-5-甲基-4,7-二氢-3H-吡咯并[2,3-d]嘧啶-6-基)硫代]苯甲酰}-L-谷氨酸4作为抗肿瘤药物。化合物3和4分别通过简洁的三步反应序列从2,4-二氨基-5-甲基吡咯并[2,3-d]嘧啶7和2-氨基-4-氧代-5-甲基吡咯并[2,3-d]嘧啶12制得。据我们所知，化合物3是首个对人二氢叶酸还原酶（DHFR）和人胸苷酸合成酶（TS）均具有强效抑制活性的2,4-二氨基经典抗叶酸剂。化合物4是针对源自刚地弓形虫（tg）的双功能酶的双DHFR-TS抑制剂。对化合物3作用机制的进一步评估表明DHFR是其主要的细胞内靶点。化合物3和4都是叶酰聚谷氨酸合成酶（FPGS）的底物。化合物3还在体外抑制了几种人肿瘤细胞系的生长，其GI50 < 10(-8) M。这项研究表明，吡咯并[2,3-d]嘧啶骨架有利于双DHFR-TS和肿瘤抑制活性，其效力由4位取代基决定。
