Gangjee Aleem, Qiu Yibin, Li Wei, Kisliuk Roy L
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, USA.
J Med Chem. 2008 Sep 25;51(18):5789-97. doi: 10.1021/jm8006933.
N-{4-[(2-Amino-6-methyl-4-oxo-3,4-dihydrothieno[2,3- d]pyrimidin-5-yl)sulfanyl]benzoyl}-L-glutamic acid (4) and nine nonclassical analogues 5-13 were synthesized as potential dual thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibitors. The key intermediate in the synthesis was 2-amino-6-methylthieno[2,3-d]pyrimidin-4(3 H)-one (16), which was converted to the 5-bromo-substituted compound 17 followed by an Ullmann reaction to afford 5-13. The classical analogue 4 was synthesized by coupling the benzoic acid derivative 19 with diethyl L-glutamate and saponification. Compound 4 is the most potent dual inhibitor of human TS (IC 50 = 40 nM) and human DHFR (IC 50 = 20 nM) known to date. The nonclassical analogues 5- 13 were moderately potent against human TS with IC 50 values ranging from 0.11 to 4.6 microM. The 4-nitrophenyl analogue 7 was the most potent compound in the nonclassical series, demonstrating potent dual inhibitory activities against human TS and DHFR. This study indicated that the 5-substituted 2-amino-4-oxo-6-methylthieno[2,3-d]pyrimidine scaffold is highly conducive to dual human TS-DHFR inhibitory activity.
合成了N-{4-[(2-氨基-6-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-5-基)硫烷基]苯甲酰基}-L-谷氨酸(4)和9种非经典类似物5-13，作为潜在的胸苷酸合成酶(TS)和二氢叶酸还原酶(DHFR)双重抑制剂。合成中的关键中间体是2-氨基-6-甲基噻吩并[2,3-d]嘧啶-4(3H)-酮(16)，将其转化为5-溴取代的化合物17，然后通过乌尔曼反应得到5-13。经典类似物4是通过将苯甲酸衍生物19与L-谷氨酸二乙酯偶联并皂化合成的。化合物4是迄今为止已知的对人TS(IC50 = 40 nM)和人DHFR(IC50 = 20 nM)最有效的双重抑制剂。非经典类似物5-13对人TS具有中等活性，IC50值范围为0.11至4.6 microM。4-硝基苯基类似物7是非经典系列中最有效的化合物，对人TS和DHFR表现出有效的双重抑制活性。这项研究表明，5-取代的2-氨基-4-氧代-6-甲基噻吩并[2,3-d]嘧啶骨架非常有利于对人TS-DHFR的双重抑制活性。
