Bioinspired total synthesis of Capsicodendrin and synthesis of Saponin derivatives for prevention and treatment of enveloped virus-mediated infectious diseases

Abstract

This thesis is divided into two chapters. Each chapter describes the total synthesis of dimeric Drimane Sesquiterpenes and the effectiveness of the newly developed antiviral agents over various SARS-CoV-2 variants hints at the broad-spectrum antiviral efficacy of saponin-based therapeutics against future coronavirus variants.

Chapter 1 describe the first total synthesis of cinnamodial-based dimer (–)-capsicodendrin. Firstly, we developed a 12-step synthetic route to access (–)-cinnamodial from 1-vinyl-2,6,6-trimethylcyclohexene. We then showed that (–)-cinnamodial can selectively dimerize to (–)-capsicodendrin under kinetically controlled basic conditions. Our observations regarding a facile conversion of (–)-capsicodendrin back to (–)-cinnamodial hint at the possibility that (–)-capsicodendrin is a chemical reservoir of insecticidal (–)-cinnamodial and Cinnamosma genus plants release it upon environmental stresses.

Chapter 2 discovered that the C3-glucose, the C28-oligosaccharide moiety that consist of (→3)-β-D-Xyl-(1→4)- α-L-Rham-(1→2)-β-D-Ara-(1→) as the last three sugar units, and the C16-hydroxyl group were critical components of saponin-based coronavirus cell entry inhibitors. These findings enabled us to develop minimal saponin-based antiviral agents that are 1.6 to 2 times more potent than the originally discovered platycodin D. We found that our saponin-based antiviral agents inhibited both the endosomal and transmembrane protease serine 2-mediated cell surface viral entries. Cell fusion assay experiment revealed that our newly developed compounds inhibit the SARS-CoV-2 entry by blocking the fusion between the viral and host cell membranes. The effectiveness of the newly developed antiviral agents over various SARS-CoV-2 variants hints at the broadspectrum antiviral efficacy of saponin-based therapeutics against future coronavirus variants.