Authors:
- Nominated by Tohoku University as an outstanding Ph.D. thesis
- Provides efficient information for a rare inhibitor of protein–protein interactions (PPIs)
- Reconfirms the potential of complicated natural products as drug seeds
- Includes supplementary material: sn.pub/extras
Part of the book series: Springer Theses (Springer Theses)
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Table of contents (5 chapters)
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Front Matter
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Back Matter
About this book
This book focuses on thielocin B1 (TB1), which was found to be an inhibitor of protein–protein interactions (PPIs) of proteasome assembling chaperone (PAC) 3 homodimer, and elucidates the mechanism by nuclear magnetic resonance (NMR) studies. Interfaces of PPIs recently have been expected to be novel therapeutic targets, while it is difficult to apply conventional methodology based on lock and key theory. The author achieved the first total synthesis of TB1 and its spin-labeled derivative to carry out NMR experiments because the supply of TB1 from natural sources was limited. Unique 2,2’,6,6’-tetrasubstituted diphenyl ether moiety of TB1 was synthesized from a depsidone skeleton by chemoselective reduction of lactone. In the process of elongating side wings, efficient formylation utilizing dichloromethyl methyl ether–silver trifluoromethanesulfonate was developed for the sterically hindered aromatic compound. NMR titration experiments and paramagnetic relaxation enhancement observation of PAC3 homodimer were performed with synthesized TB1 and its molecular probe, respectively. The results of the above NMR studies and additional in silico docking studies suggested that TB1 promotes the dissociation to monomeric PAC3 after interaction with PAC3 homodimer. The rare mechanism shown in this book indicates a potential novel drug target in the interfaces of PPIs with no cavity or groove.
Authors and Affiliations
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Max-Planck Institute of Molecular Physiology, Dortmund, Germany
Kosuke Ohsawa
Bibliographic Information
Book Title: Total Synthesis of Thielocin B1 as a Protein-Protein Interaction Inhibitor of PAC3 Homodimer
Authors: Kosuke Ohsawa
Series Title: Springer Theses
DOI: https://doi.org/10.1007/978-4-431-55447-9
Publisher: Springer Tokyo
eBook Packages: Chemistry and Materials Science, Chemistry and Material Science (R0)
Copyright Information: Springer Japan 2015
Hardcover ISBN: 978-4-431-55446-2Published: 26 January 2015
Softcover ISBN: 978-4-431-56287-0Published: 06 October 2016
eBook ISBN: 978-4-431-55447-9Published: 13 January 2015
Series ISSN: 2190-5053
Series E-ISSN: 2190-5061
Edition Number: 1
Number of Pages: XIII, 109
Number of Illustrations: 70 b/w illustrations, 14 illustrations in colour
Topics: Organic Chemistry, Pharmacy, Medicinal Chemistry