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Total Synthesis of JBIR-141 and Its Analogues: Potent Inhibitors of Forkhead Box O3 (FOXO3)
Hidetoshi Ban1, Kotaro Yasoshima1, Kosuke Ohsawa1,2
1Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-aoba, Aramaki, Sendai980-8578, Japan.
Abstract:
The total synthesis of JBIR-141 and its analogues was achieved through a convergent assembly of three fragments. This synthesis successfully addressed several challenges arising from a highly acid-sensitive oxazoline, a reactive nitrosohydroxyamino group, and an epimerization-prone tetramic acid. The developed synthetic route enabled access to 25-methyl/17-methyl derivatives as potent/stabilized FOXO3 inhibitors. This study provides a robust platform for structure-activity relationship studies and future target identification in chronic myelogenous leukemia therapeutics.
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