Scientific Publications by FDA Staff

J Am Chem Soc 2019 Jan 23;141(3):1312-23

Chemical synthesis enables structural reengineering of aglaroxin c leading to inhibition bias for hepatitis C viral infection.

Zhang WH, Liu SF, Maiga RI, Pelletier J, Brown LE, Wang TT, Porco JA

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.