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

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....

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2008-09, Vol.16 (18), p.8661-8669
Main Authors: Nakashima, Hitomi, Uto, Yoshihiro, Nakata, Eiji, Nagasawa, Hideko, Ikkyu, Kazuhiro, Hiraoka, Noriko, Nakashima, Kouichiro, Sasaki, Yuki, Sugimoto, Hiroshi, Shiro, Yoshitsugu, Hashimoto, Toshihiro, Okamoto, Yasuko, Asakawa, Yoshinori, Hori, Hitoshi
Format: Article
Language:English
Subjects:
1-Methyl-tryptophan (1MT)
1MT-TPZ hybrids
Animals
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Biological and medical sciences
Cell Hypoxia - drug effects
Cell Line, Tumor
Drug Screening Assays, Antitumor
General aspects
Hypoxic-neoplastic cells
Indoleamine 2,3-dioxygenase
Indoleamine-Pyrrole 2,3,-Dioxygenase - antagonists & inhibitors
Medical sciences
Mice
Pharmacology. Drug treatments
Structure-Activity Relationship
Triazines - chemical synthesis
Triazines - pharmacology
Tryptophan - analogs & derivatives
Tryptophan - chemical synthesis
Tryptophan - pharmacology
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Summary: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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2008.07.087