Discovery, Synthesis, and Biological Evaluation of Anaenamides C and D from a New Marine Cyanobacterium, Hormoscilla sp

Our ongoing efforts to explore the chemical space associated with marine cyanobacteria from coral reefs of Guamhave yielded two new members of the anaenamide family ofnatural products, anaenamides C (3)and D (4). Thesecompounds were isolated from a novelHormoscillasp. (VPG16-58). Our phylogenetic profiling (16S rDNA) of this cyanobacte-rium indicated that VPG16-58 is taxonomically distinct from thepreviously reported producer of the anaephenes, VPG16-59(Hormoscillasp.), and other previously documented species of the genusHormoscilla. The planar structures of3and4weredetermined via spectroscopic methods, and absolute configurations of the alpha-hydroxy acids were assigned by enantioselective HPLCanalysis. To address the requirement for sufficient material for testing, wefirst adapted our published linear synthetic approach for1and2to generate anaenoic acid (7), which served as a point for diversification, providing the primary amides3and4from syntheticintermediates5and6, respectively. The compounds were then tested for effects on HCT116 colon cancer cell viability and in anARE-luciferase reporter gene assay for Nrf2 modulation using HEK293 human embryonic kidney cells. Ourfindings indicate that, incontrast to cytotoxic methyl esters1and2, the primary amides3and4activate the Nrf2 pathway at noncytotoxic concentrations.Overall, our data suggest that the anaenamide scaffold is tunable to produce differential biological outcomes.

Automated summary

Our ongoing efforts in exploring the chemical space of marine cyanobacteria have led to the discovery of two new members of the anaenamide family. These compounds, isolated from a novel cyanobacterium, show potential activation of the Nrf2 pathway at noncytotoxic concentrations.