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. 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.
Nakashima
Hitomi
H
Department of Life System, Institute of Technology and Science, Graduate School, The University of Tokushima, Minamijosanjimacho-2, Tokushima 770-8506, Japan.
Uto
Yoshihiro
Y
Nakata
Eiji
E
Nagasawa
Hideko
H
Ikkyu
Kazuhiro
K
Hiraoka
Noriko
N
Nakashima
Kouichiro
K
Sasaki
Yuki
Y
Sugimoto
Hiroshi
H
Shiro
Yoshitsugu
Y
Hashimoto
Toshihiro
T
Okamoto
Yasuko
Y
Asakawa
Yoshinori
Y
Hori
Hitoshi
H
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors*; D051379:Mice; D013329:Structure-Activity Relationship; D000077704:Tirapazamine; D014227:Triazines / Q000138:chemical synthesis / Q000494:pharmacology*; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D000970:Antineoplastic Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014227:Triazines; D000077704:Tirapazamine; D014364:Tryptophan