Studies on Practical Strategy for Peptide-lead Drug Discovery and Development

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The four year research project has been focused on the development of stereoselective synthetic methods for peptide-lead drug discovery and its application for several peptidic drug candidates as follows :1. One-flask reaction composed of aza-Payne rearrangement and consecutive epoxy-ring opening was developed for stereoselective synthesis of key substructure of substrate transition state-based protease inhibitors. The new method has been applied to the discovery of highly active HIV protease inhibitors even potent to multi-drug resistant HIV-1 virus clinical strains. The new method coupled with O'N-acyl transfer reaction and solid phase organic synthesis found the versatile utility to combinatorial chemistry and applied to structure activity-relationship study on β-secretase relevant to Alzheimer disease.2. Theoretical and practical investigation on stereoselecive synthesis of alkene-type dipeptide isosteres and its application to biologically active peptides (bombesin, integrin antagonist, CXCR4 antagonist, nociceptin) met with the great achievements beyond the initial research plans, as follows :1) Establishment of totally stereo-controlled synthetic process for (E)-alkene dipepitde isosteres, EADI, starting from amino acids and successful application to peptide-lead agonists ＆ antagonists.2) Stereoselective synthesis of EADIs with trisubstituted-and tetrasubstituted alkenes based on organocopper chemistry.3) Stereoselective synthesis of (Z)-fluoroalkene dipeitide isosteres based on organocopper mediated reduction oxidative alkylation.4) Stereoselective synthesis of highly α-functionalised EADI based on anti-SN2' reaction by organozinc copper complex.