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Synthesis of an Indoleamine-2,3-dioxygenase-1 (IDO1) Inhibitor
Discovery of Hydroxyamidine Based Inhibitors of IDO1 for Cancer Immunotherapy with Reduced Potential for Glucuronidation.
ACS Med. Chem. Lett. 2020;
18 March 2020 (online)
Indoleamine-2,3-dioxygenase-1 (IDO1) is strongly involved in tumor immune resistance. The immune suppressive effect of IDO1 results from its capacity to degrade tryptophan to N-formylkyurenine, the first and rate-limiting step of the kyurenine pathway. The target molecule N is a low-nanomolar IDO1 inhibitor.
Reaction of aldoxime F with N-chlorosuccinimide (NCS) afforded N-hydroxycarbimidoyl chloride G. Treatment of G with 3-chloroaniline followed by hydroxyamidine cyclization using 1,1′-carbonyldiimidazole (CDI) and Boc deprotection afforded the key amino intermediate K.