Total Synthesis of JBIR-141 and Its Analogues: Potent Inhibitors of Forkhead Box O3 (FOXO3)
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.
Authors
- Teppei Kawahara (ORCID: https://orcid.org/0000-0001-5140-4724)
- Hiroyuki Yamakoshi (ORCID: https://orcid.org/0000-0002-9263-577X)
- Kosuke Ohsawa (ORCID: https://orcid.org/0000-0002-7895-1573)
- Noritaka Kagaya (ORCID: https://orcid.org/0000-0002-0622-983X)
- Kazuo Shin‐ya (ORCID: https://orcid.org/0000-0002-4702-0661)
- M. Suzuki
- Kotaro Yasoshima
- Masahito Yoshida (ORCID: https://orcid.org/0000-0002-0252-7637)
- Takayuki Doi (ORCID: https://orcid.org/0000-0002-8306-6819)
- Hidetoshi Ban
Institutions
- University of Tsukuba (JP)
- Tohoku University (JP)
- Juntendo University (JP)
- Japan Biological Informatics Consortium (JP)
- Juntendo University Urayasu Hospital (JP)
- National Institute of Advanced Industrial Science and Technology (JP)
Publication Details
- Journal
- Organic Letters
- Published
- 2026-07-18
- DOI
- https://doi.org/10.1021/acs.orglett.6c02149
- Primary Topic
- FOXO transcription factor regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Japan Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science