Flavaglines as cross-kingdom translation inhibitors: Heavy halides at C6 potentiate antineoplastic, antiviral, and antifungal activities.

Abstract

The growing prevalence of cancer, coupled with the rise of multidrug-resistant pathogens, presents a formidable challenge to modern medicine. The flavagline class of secondary metabolites has been shown to possess a unique capacity to target multiple conserved pathways across various human malignancies and microbial pathogens. While numerous structure-activity relationship (SAR) campaigns have established trends with respect to specific indications, cross-kingdom comparative analyses have not been reported to date. In this work, a structurally diverse library comprising 17 novel and 5 natural flavagline analogues, alongside 3 known derivatives, was synthesized and systematically screened for cytotoxicity against five cancer cell lines, inhibition of Enterovirus A71 (EV-A71), and activity against multidrug-resistant Candida and Aspergillus pathogens. It was found that introduction of heavy halides (Br or I) at the 6 position significantly potentiates the in vitro biological activities of all tested flavagline chemotypes. Immunoblotting experiments, circumstantial evidence, and molecular docking suggest that the enhanced activity of C6-Br derivatives is consistent with enhanced DEAD-box helicase (eIF4A or DDX3)-RNA clamping. Additionally, the putative flavagline biogenetic precursor chemotypes, aglains and flavonols, were shown to exhibit significant antiviral and antifungal activities. This is the first systematic SAR study directly comparing the anticancer and antipathogenic activities of flavagline derivatives, or any other known translation inhibitors.