Synthesis of Kynapcins and Telephoric Acids as Prolyl Endopeptidase Inhibitors of Anti-Dementia Drugs

Abstract

Prolyl endopeptidase (PEP), a serine protease, is known to cleave a peptide substrate on the C-terminal side of a proline residue. Additionally, the PEP activity of Alzheimer's patients has been found to be significantly higher than that of the normal person. Therefore, the search for PEP inhibitors as anti-dementia drugs, which may play a crucial role in curing Alzheimer's disease, has attracted significant attention from the synthetic, biological, and medicinal comunities. Recently, Song et al. reported that two novel PEP inhibitors, benzofuran dimer kynapcin-24 (1) (IC50, 1.14 μM) and pentacyclic polyozellin, as well as related compounds, were isolated from Polyozellus multiflex Murr. On the other hand, although propeptin (IC50, 1.1 μM) has inhibition similar to 1, it is a hydrophilic and large molecular weight peptide, which may make it difficult to penetrate the blood-brain barrier. With the difficulty of propeptin as a PEP inhibitor and the promise shown by drugs such as 1, The synthesis of kynapcin-24, which can be isolated from the Korean mushroom Polyozellus multiflex Murr, is achieved in 12% overall yield from commercially available 3,4-dihydroxybenzaldehyde by a route in which the longest linear sequence is only 14 steps. The key transformations in the synthesis are the Cu-mediated and Pd-catalyzed coupling reactions of benzofuranyl iodide 12 with stannane 15, and 5-endo-dig iodocyclization of a phenol propargyl ether. In addition, telephoric acids have also synthesized in high yields. Finally, the molecular model was examined the interactions of proteins and ligands as well.