Synthesis and biological activity of 1-methyl-tryptophan-tirapazamine hybrids as hypoxia-targeting indoleamine 2,3-dioxygenase inhibitors

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• 作者：Hitomi Nakashima ; Yoshihiro Uto ; Eiji Nakata ; Hideko Nagasawa ; Kazuhiro Ikkyu ; Noriko Hiraoka ; Kouichiro Nakashima ; Yuki Sasaki ; Hiroshi Sugimoto ; Yoshitsugu Shiro ; Toshihiro Hashimoto ; Yasuko Okamoto
• 关键词：Indoleamine 2 ; 3-dioxygenase ; 1-Methyl-tryptophan (1MT) ; 1MT-TPZ hybrids ; Hypoxic-neoplastic cells
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2008
• 出版时间：15 September 2008
• 年：2008
• 卷：16
• 期：18
• 页码：8661-8669
• 全文大小：439 K

文摘

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.