Design, synthesis, and X-ray crystal structure of classical and nonclassical 2-amino-4-oxo-5-substituted-6-ethylthieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors and as potential antitumor agents.
Design, synthesis, and X-ray crystal structure of classical and nonclassical 2-amino-4-oxo-5-substituted-6-ethylthieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors and as potential antitumor agents.
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DOI：
10.1021/jm900490a
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发表时间：
2009-08-13
影响因子：
7.3
通讯作者：
Makin J
中科院分区：
文献类型：
--
作者：
Gangjee A;Li W;Kisliuk RL;Cody V;Pace J;Piraino J;Makin J
合成了 N-{4-[(2-氨基-6-乙基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-5-基)硫代]苯甲酰}-L-谷氨酸 2 和十三个非经典类似物 2a-2m，作为潜在的双胸苷酸合酶 (TS) 和二氢叶酸还原酶 (DHFR) 抑制剂和抗肿瘤药物。合成中的关键中间体是2-氨基-6-乙基-5-碘噻吩并[2,3-d]嘧啶-4(3H)-one, 7，其5位上连接有各种芳基硫醇。 8与L-谷氨酸二乙酯偶联并皂化得到2。2和1（2的6-甲基类似物）、DHFR和NADPH的X射线晶体结构首次表明噻吩并[2,3-d]嘧啶环以“叶酸”模式结合。化合物 2 是人 TS (IC50 = 54 nM) 和人 DHFR (IC50 = 19 nM) 的优异双重抑制剂，并且针对培养中的肿瘤细胞提供纳摩尔级 GI50 值。与 6-甲基类似物 1 相比，2 中的 6-乙基取代增加了效力（提高了两到三个数量级）以及体外肿瘤抑制谱。一些非经典类似物是弓形虫 DHFR 的有效和选择性抑制剂。
N-{4-[(2-amino-6-ethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl)thio]benzoyl}-L-glutamic acid 2 and thirteen nonclassical analogues 2a–2m were synthesized as potential dual thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibitors and as antitumor agents. The key intermediate in the synthesis was 2-amino-6-ethyl-5-iodothieno[2,3-d]pyrimidin-4(3H)-one, 7, to which various aryl thiols were attached at the 5-position. Coupling 8 with L-glutamic acid diethyl ester and saponification afforded 2. X-ray crystal structure of 2 and 1 (the 6-methyl analogue of 2), DHFR and NADPH showed for the first time that the thieno[2,3-d]pyrimidine ring binds in a “folate” mode. Compound 2 was an excellent dual inhibitor of human TS (IC50 = 54 nM) and human DHFR (IC50 = 19 nM), and afforded nanomolar GI50 values against tumor cells in culture. The 6-ethyl substitution in 2 increases both the potency (by two- to three-orders of magnitude) as well as the spectrum of tumor inhibition in vitro compared to the 6-methyl analogue 1. Some of the nonclassical analogues were potent and selective inhibitors of DHFR from Toxoplasma gondii.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, 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：
5.8
作者：
Hawser, S;Lociuro, S;Islam, K
通讯作者：
Islam, K
DOI：
10.1107/s0907444994003112
发表时间：
1994-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
BAILEY, S
通讯作者：
BAILEY, S
影响因子：
5.8
作者：
GIBSON, W;BISSET, GMF;JACKMAN, AL
通讯作者：
JACKMAN, AL