著作: Nakashima Hitomi/Ikkyu Kazuhiro/Nakashima Kouichiro/Sano Keiichiro/[宇都 義浩]/[中田 栄司]/[永澤 秀子]/Sugimoto Hiroshi/Shiro Yoshitsugu/Nakagawa Yoshinori/[堀 均]/Design of novel hypoxia-targeting IDO hybrid inhibitors conjugated with an unsubstituted L-Trp as an IDO affinity moiety/ISOTT2008 (2008 International Society on Oxygen Transport to Tissue Conference)
(英) Design of novel hypoxia-targeting IDO hybrid inhibitors conjugated with an unsubstituted L-Trp as an IDO affinity moiety
(英) Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial and rate limiting step of L-Tryptophan (L-Trp) catabolism in the kynurenine pathway. IDO expresses in many neoplasms, and play a role in immunosuppression. IDO is activated only reductive or hypoxic conditions, because the heme iron of active site is easily oxidized to its inactive form. Hypoxic neoplastic cells indicate chemo- and radioresistances and also cause neoplasm' progression, invasion and metastasis. Previously we focused to the mode of activation of IDO only in hypoxic and reductive condition to design hypoxia-targeting IDO hybrid inhibitors, which constituted an IDO inhibitor 1-methyl-tryptophan (1MT) and hypoxic cytotoxin tirapazamine (TPZ), such as TX-2236, TX-2235, TX-2228 and TX-2234. They were good hypoxia-targeting IDO inhibitors. 1MT-TPZ hybrids inhibited IDO uncompetitively. Thus, it suggests that 1MT-TPZ hybrids were able to bind the only enzyme-substrate complex, not to bind the active site. In this study, we present here the novel design and syntheses of 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 (n = 4, monoxide), 2 (n = 4, dioxide), 3 (n = 5, monoxide), and 4 (n = 5, dioxide). These L-Trp-TPZ hybrids were synthesized from 3-chlorinated TPZ monoxide with various length alkyldiamines to give the corresponding amine derivatives, which were conjugated with Boc-L-Trp to give the L-Trp-TPZ monoxide hybrids 1 and 3. L-Trp-TPZ dioxide hybrids 2 and 4 were also synthesized from the corresponding TPZ-dioxide trifluoroacetamide intermediates. L-Trp-TPZ hybrids were good competitive inhibitors of IDO. Thus, it suggests that these L-Trp-TPZ hybrids were able to bind the active site. In conclusion, we discovered IDO hybrid inhibitors conjugated with an unsubstituted L-Trp as an IDO affinity moiety. Additionally we are under evaluation of their hypoxic cytotoxicity to develop hypoxia-targeting IDO hybrid inhibitors as our final goal.
(英) ISOTT2008 (2008 International Society on Oxygen Transport to Tissue Conference)
|年月日||必須||2008年 8月 6日|