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

Abstract

As a unique rocaglate (flavagline) natural product, aglaroxin C displays intriguing biological activity by inhibiting HCV 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 forty 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 HCV 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.

Heat Shock Factor 1-dependent extracellular matrix remodeling mediates the transition from chronic intestinal inflammation to colon cancer

“…For immortalized or primary MEFs the medium was changed every day, for 7 or 12 days, for primary colon fibroblasts, half of the medium was changed for 3-5 days, after which the glass slides were removed from the plate carefully and imaged using SHG for collagen imaging. For HSF1 inhibition, CMLD011866 (aglaroxin C 40,41 ) was first optimized to determine the maximal dose at which cell viability is not compromised (500 nM). Based on this optimization, 3 nM CMLD011866 was added daily to primary WT colon fibroblasts for 3-5 days and SHG imaging was performed.…”

“…8a), suggesting that HSF1 does not play an essential role in contractility. To demonstrate that ECM deposition by colon fibroblasts is HSF1-dependent, we used the synthetic small molecule CMLD011866 ((-)-aglaroxin C [40][41][42] , Fig. 7g).…”

“…Chemical reagents. ((-)-Aglaroxin C (CMLD011866) was synthesized according to published protocols 40,41 .…”

Prohibitin ligands: a growing armamentarium to tackle cancers, osteoporosis, inflammatory, cardiac and neurological diseases

“…These events are inhibited by several flavaglines, and in particular aglaroxin C (6), which displays a potency and therapeutic index superior to that of rocaglamide (1) and other flavaglines. Optimization of aglaroxin C led to the development of CMLD012043 (9) and CMLD012044 (10), which show an enhanced inhibition of HCV infection with low cytotoxicity [56]. These two compounds inhibit HCV viral entry into cells, but not HCV RNA replication and mRNA translation, suggesting that these effects are mediated by an action on PHBs rather than eIF4A.…”

Flavaglines as natural products targeting eIF4A and prohibitins: From traditional Chinese medicine to antiviral activity against coronaviruses

“…1 ) were found to prevent the localization of PHBs at the cell surface, and consequently to block C-RAF activation and to reduce HCV infection with an EC 50 of 4 and 0.04 nM (incubation of 48 h in Huh7.5.1 cells) respectively. Thereafter Porco and collaborators synthesized aglaroxin C analogues and showed that two of them, CMLD012043 ( 8 ) and CMLD012044 ( 9 ), showed 3-fold greater inhibition of HCV infection in comparison to aglaroxin C and also with very low cytotoxicity [ 16 ].…”