title: Design of novel hypoxia-targeting IDO hybrid inhibitors conjugated with an unsubstituted L-TRP as an IDO affinity moiety.
abstract: 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 hybrids 1 (TX-2274), 2 (UTX-3), 3 (UTX-4), and 4 (UTX-2). TPZ-monoxide hybrids 1 and 3 were good competitive IDO inhibitors, while TPZ hybrids 2 and 4 were uncompetitive IDO inhibitors. Among them TPZ-monoxide hybrid 1 have the strongest IDO inhibitory activity. It suggests that TPZ-monoxide hybrids 1 and 3 are able to bind the active site of IDO, TPZ hybrids 2 and 4 are able to bind the enzyme-substrate complex. We proposed the possible mechanism of action of TPZ hybrid 2 that may first affect as a hypoxic cytotoxin, and then metabolized to TPZ-monoxide hybrid 1, which may do as an IDO inhibitor more effectively than its parent TPZ hybrid 2.
authors.affiliation: Department of Life System, Institute of Technology and Science, Graduate School, The University of Tokushima, Tokushima 770-8506, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Nakashima
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ikkyu
authors.forename: Kouichiro
authors.initials: K
authors.lastname: Nakashima
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Sano
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Uto
authors.forename: Eiji
authors.initials: E
authors.lastname: Nakata
authors.forename: Hideko
authors.initials: H
authors.lastname: Nagasawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Shiro
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hori
mesh_terms: D015687:Cell Hypoxia / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors*; D007700:Kinetics; D000077704:Tirapazamine; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014364:Tryptophan / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014227:Triazines; D000077704:Tirapazamine; D014364:Tryptophan