Design of novel hypoxia-targeting IDO hybrid inhibitors conjugated with an unsubstituted L-TRP as an IDO affinity moiety.
Design of novel hypoxia-targeting IDO hybrid inhibitors conjugated with an unsubstituted L-TRP as an IDO affinity moiety.
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DOI：
10.1007/978-1-4419-1241-1_60
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发表时间：
2010
影响因子：
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通讯作者：
H. Nakashima;Kazuhiro Ikkyu;K. Nakashima;Keiichiro Sano;Y. Uto;Eiji Nakata;H. Nagasawa;H. Sugimoto;Y. Shiro;Y. Nakagawa;H. Hori
中科院分区：
文献类型：
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作者：
H. Nakashima;Kazuhiro Ikkyu;K. Nakashima;Keiichiro Sano;Y. Uto;Eiji Nakata;H. Nagasawa;H. Sugimoto;Y. Shiro;Y. Nakagawa;H. Hori
本论文设计、合成了一系列具有缺氧靶向作用的IDO杂合抑制剂，包括L-Trp-TPZ杂合物1（TX-2274）、2（UTX-3）、3（UTX-4）和4（UTX-2）。TPZ-一氧化物杂合体1和3是良好的竞争性IDO抑制剂，而TPZ杂合体2和4是非竞争性IDO抑制剂。其中TPZ-monoxide hybrid 1的IDO抑制活性最强。说明TPZ-一氧化物杂交体1和3能结合IDO的活性位点，TPZ杂交体2和4能结合酶-底物复合物。我们提出了TPZ hybrid 2的可能作用机制，其可能首先作为缺氧细胞毒素发挥作用，然后代谢为TPZ-一氧化物hybrid 1，其可能比其亲本TPZ hybrid 2更有效地作为IDO抑制剂。
We presented here design, syntheses and inhibitory activities of novel hypoxia-targeting IDO hybrid inhibitors conjugated with an unsubstituted L-Trp as an IDO affinity moiety without inhibitor 1MT, such as L-Trp-TPZ hybrids1(TX-2274),2(UTX-3),3(UTX-4), and4(UTX-2). TPZ-monoxide hybrids1and3were good competitive IDO inhibitors, while TPZ hybrids2and4were uncompetitive IDO inhibitors. Among them TPZ-monoxide hybrid1have the strongest IDO inhibitory activity. It suggests that TPZ-monoxide hybrids1and3are able to bind the active site of IDO, TPZ hybrids2and4are able to bind the enzyme-substrate complex. We proposed the possible mechanism of action of TPZ hybrid2that may first affect as a hypoxic cytotoxin, and then metabolized to TPZ-monoxide hybrid1, which may do as an IDO inhibitor more effectively than its parent TPZ hybrid2.