Synthesis and biological activity of 1-methyl-tryptophan-tirapazamine hybrids as hypoxia-targeting indoleamine 2,3-dioxygenase inhibitors.
Synthesis and biological activity of 1-methyl-tryptophan-tirapazamine hybrids as hypoxia-targeting indoleamine 2,3-dioxygenase inhibitors.
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DOI：
10.1016/j.bmc.2008.07.087
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发表时间：
2008-09
影响因子：
3.5
通讯作者：
H. Nakashima;Y. Uto;Eiji Nakata;H. Nagasawa;Kazuhiro Ikkyu;N. Hiraoka;K. Nakashima;Yuki Sasaki;H. Sugimoto;Y. Shiro;T. Hashimoto;Y. Okamoto;Y. Asakawa;H. Hori
中科院分区：
文献类型：
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作者：
H. Nakashima;Y. Uto;Eiji Nakata;H. Nagasawa;Kazuhiro Ikkyu;N. Hiraoka;K. Nakashima;Yuki Sasaki;H. Sugimoto;Y. Shiro;T. Hashimoto;Y. Okamoto;Y. Asakawa;H. Hori
我们已经设计并合成了新的缺氧肿瘤细胞靶向吲哚胺2，3-双加氧酶（IDO）抑制剂。制备了1-甲基色氨酸（1 MT）-替拉扎明（TPZ，3-氨基-1，2，4-苯并三嗪1，4-二氧化物）杂合抑制剂，包括1（TX-2236）、2（TX-2235）、3（TX-2228）和4（TX-2234）。所有这些化合物都是非竞争性IDO抑制剂。TPZ-一氧化物杂合体1和3显示出比TPZ杂合体2和4更高的IDO抑制活性。在这些杂交体中，杂交体1是最有效的IDO抑制剂。TPZ杂合体2和4对EMT 6/KU细胞的缺氧选择性细胞毒作用强于TPZ。这些数据表明TPZ杂合物2和4可能通过其双重生物学功能起作用：首先，它们在缺氧细胞中充当缺氧细胞毒素，然后代谢成其TPZ-一氧化物（3-氨基-1，2，4-苯并三嗪1-氧化物）杂合物，其充当IDO抑制剂。
We have designed and synthesized new hypoxic-neoplastic cells-targeted indoleamine 2,3-dioxygenase (IDO) inhibitors. 1-Methyl-tryptophan (1MT)-tirapazamine (TPZ, 3-amino-1,2,4-benzotriazine 1,4-dioxide) hybrid inhibitors including 1 (TX-2236), 2 (TX-2235), 3 (TX-2228), and 4 (TX-2234) were prepared. All of these compounds were uncompetitive IDO inhibitors. TPZ-monoxide hybrids 1 and 3 showed higher IDO inhibitory activities than TPZ hybrids 2 and 4. Among these hybrids, hybrid 1 was the most potent IDO inhibitor. TPZ hybrids 2 and 4 showed stronger hypoxia-selective cytotoxicity than TPZ to EMT6/KU cells. These data suggest that TPZ hybrids 2 and 4 may act through their dual biological functions: first, they function as hypoxic cytotoxins in hypoxic cells, and then are metabolized to their TPZ-monoxide (3-amino-1,2,4-benzotriazine 1-oxide) hybrids, which function as IDO inhibitors.