Design of Novel Hypoxia-Targeting IDO Hybrid Inhibitors Conjugated with an Unsubstituted L-TRP as an IDO Affinity Moiety

• Published in: Advances in experimental medicine and biology Vol. 662; pp. 415 - 421
• Main Authors: Nakashima, Hitomi, Ikkyu, Kazuhiro, Nakashima, Kouichiro, Sano, Keiichiro, Uto, Yoshihiro, Nakata, Eiji, Nagasawa, Hideko, Sugimoto, Hiroshi, Shiro, Yoshitsugu, Nakagawa, Yoshinori, Hori, Hitoshi
• Format: Book Chapter Journal Article
• Language: English
• Published: Boston, MA Springer US 2010
• Series: Advances in Experimental Medicine and Biology
• Subjects: Cell Hypoxia - drug effects; Conjugation Reaction; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Heme Iron; Humans; Indole Moiety; Indoleamine-Pyrrole 2,3,-Dioxygenase - antagonists & inhibitors; Kinetics; Kynurenine Pathway; Triazines - chemical synthesis; Triazines - chemistry; Triazines - pharmacology; Tryptophan - metabolism; Uncompetitive Inhibition
• ISBN: 1441912398; 9781441912398
• ISSN: 0065-2598
• DOI: 10.1007/978-1-4419-1241-1_60

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.