Potent dual thymidylate synthase and dihydrofolate reductase inhibitors: classical and nonclassical 2-amino-4-oxo-5-arylthio-substituted-6-methylthieno[2,3-d]pyrimidine antifolates.
Potent dual thymidylate synthase and dihydrofolate reductase inhibitors: classical and nonclassical 2-amino-4-oxo-5-arylthio-substituted-6-methylthieno[2,3-d]pyrimidine antifolates.
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DOI：
10.1021/jm8006933
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发表时间：
2008-09-25
影响因子：
7.3
通讯作者：
Kisliuk RL
中科院分区：
文献类型：
--
作者：
Gangjee A;Qiu Y;Li W;Kisliuk RL
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(3H)-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 (IC50 = 40 nM) and human DHFR (IC50 = 20 nM) known to date. The nonclassical analogues 5–13 were moderately potent against human TS with IC50 values ranging from 0.11 to 4.6 µM. 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.
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影响因子：
5.8
作者：
Hawser, S;Lociuro, S;Islam, K
通讯作者：
Islam, K
影响因子：
7.3
作者：
Gangjee, A;Yu, JM;Queener, SF
通讯作者：
Queener, SF
影响因子：
7.3
作者：
GANGJEE, A;DEVRAJ, R;KISLIUK, RL
通讯作者：
KISLIUK, RL
影响因子：
2.4
作者：
ELSLAGER, EF;JACOB, P;WERBEL, LM
通讯作者：
WERBEL, LM
影响因子：
7.3
作者：
Gangjee, A;Mavandadi, F;Queener, SF
通讯作者：
Queener, SF