Laurie Askenatzis

Herein, we present the first synthesis of hybrid molecules combining the pharmacophores of two natural compounds, schweinfurthin E (SW-E) and the glycosidic moiety of OSW-1. These hybrids were designed leveraging the complementary binding of SW-E and OSW-1 to their biological target. The synthetic process highlights, in particular, one-pot functionalization and glycosylation of an L-arabinose unit using a D-xyloside donor and a CuAAC click reaction involving a polyfunctionalized prenylated stilbene derived from SW-E. The cytotoxicity of the four SW-E and OSW-1 hybrids is also reported, two of them being much more cytotoxic than SW-E on a glioblastoma cancer cell line. Finally, a molecular modeling study is conducted to rationalize the biological results obtained.

Hijacking host cell lipid homeostatic pathways is a hallmark of infection by RNA-positive viruses. A key protein exploited by these viruses to facilitate replication is the lipid exchanger Oxysterol-binding protein (OSBP), making it an attractive target for antiviral strategies. However, the known OSBP ligands are poorly selective, and those of natural origin, referred to as ORPphilins, exhibit pronounced cytotoxicity. Here, we describe macarangin B, a new racemic flavonoid isolated from a Vietnamese bushy tree. This compound features a rare hydroxy-hexahydroxanthene moiety that confers the ability to bind OSBP. Using a bio-inspired method, we performed the total synthesis of both (R, R, R) and (S, S, S) enantiomers, allowing us to examine their distinct interaction with OSBP, based on their unique optical properties. Together, experimental and computational approaches indicate that the (R, R, R) enantiomer has the highest affinity for OSBP. We show that replication of the health-threatening Flavivirus Zika virus in infected human cells is strongly reduced by treatment with (R, R, R)-macarangin B, which selectively targets OSBP. Importantly, both enantiomers exhibit significantly decreased cytotoxicity when compared to the previously characterized ORPphilins, positioning (R, R, R)-macarangin B as a promising lead for the development of a novel family of antivirals.