This book focuses on thielocin B1 (TB1), which was found to be an inhibitor of proteinprotein 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 ethersilver 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.

Nominated by Tohoku University as an outstanding Ph.D. thesis Provides efficient information for a rare inhibitor of proteinprotein interactions (PPIs) Reconfirms the potential of complicated natural products as drug seeds Includes supplementary material: sn.pub/extras

Inhalt

Introduction.- Total Synthesis of Thielocin B1 and NMR Chemical Shift Perturbation Experiments with PAC3 Homodimer.- Synthesis of Spin-labeled Thielocin B1 and Observation of Paramagnetic Relaxation Enhancement Effects.- An Improved Method for the Direct Formylation ob Substituted Benzenes Using Dichloromethyl Methyl Ether-Silver Trifluoromethanesulfonate.- Conclusions.