Mohebbi Shohreh, Falcón-Pérez Juan Manuel, González Esperanza, Millet Oscar, Mato Jose Maria, Kobarfard Farzad
Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran 14155-6153, Iran.
Chem Pharm Bull (Tokyo). 2012;60(1):70-8. doi: 10.1248/cpb.60.70.
A series of 2-substituted-4,6-diaminipyrimidine derivatives were synthesized and evaluated for their dihydrofolate reductase (DHFR) inhibitory activity. Saturation transfer difference (STD) (1)H-NMR experiments were used to probe the binding characteristics of the compounds with human DHFR enzyme. The most potent molecules, 12 and 15, in enzyme assay study showed the best results in STD experiments indicating their intimate interaction with the receptor. The docking studies were followed to explain the structural basis for the observed interaction between the ligands and DHFR. All the compounds were also assayed in vitro for their growth inhibitory activity on MCF-7, HepG2, SKHep1, and Hela tumor cell lines. Compounds 16, 17, and 22 demonstrated the most potent in vitro anti-proliferative activity among the others.
合成了一系列2-取代-4,6-二氨基嘧啶衍生物，并对其二氢叶酸还原酶（DHFR）抑制活性进行了评估。采用饱和转移差（STD）（1）H-NMR实验来探究这些化合物与人DHFR酶的结合特性。在酶活性测定研究中，最具活性的分子12和15在STD实验中显示出最佳结果，表明它们与受体有紧密的相互作用。随后进行了对接研究，以解释观察到的配体与DHFR之间相互作用的结构基础。还对所有化合物进行了体外实验，检测其对MCF-7、HepG2、SKHep1和Hela肿瘤细胞系的生长抑制活性。化合物16、17和22在其他化合物中表现出最强的体外抗增殖活性。
