Chemical Synthesis Enables Structural Reengineering of Aglaroxin C Leading to Inhibition Bias for Hepatitis C Viral Infection

As a unique rocaglate (flavagline)
natural product, aglaroxin C
displays intriguing biological activity by inhibiting hepatitis C
viral entry. To further elucidate structure–activity relationships
and diversify the pyrimidinone scaffold, we report a concise synthesis
of aglaroxin C utilizing a highly regio­selective pyrimidinone
condensation. We have prepared more than 40 aglaroxin C analogues
utilizing various amidine condensation partners. Through biological
evaluation of analogues, we have discovered two lead compounds, CMLD­012043
and CMLD­012044, which show preferential bias for the inhibition
of hepatitis C viral entry vs translation inhibition. Overall, the
study demonstrates the power of chemical synthesis to produce natural
product variants with both target inhibition bias and improved therapeutic
indexes.