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 Guam have yielded two new members of the anaenamide family of natural products, anaenamides C (3) and D (4). These compounds were isolated from a novel Hormoscilla sp. (VPG16-58). Our phylogenetic profiling (16S rDNA) of this cyanobacterium indicated that VPG16-58 is taxonomically distinct from the previously reported producer of the anaephenes, VPG16-59 (Hormoscilla sp.), and other previously documented species of the genus Hormoscilla. The planar structures of 3 and 4 were determined via spectroscopic methods, and absolute configurations of the α-hydroxy acids were assigned by enantioselective HPLC analysis. To address the requirement for sufficient material for testing, we first adapted our published linear synthetic approach for 1 and 2 to generate anaenoic acid (7), which served as a point for diversification, providing the primary amides 3 and 4 from synthetic intermediates 5 and 6, respectively. The compounds were then tested for effects on HCT116 colon cancer cell viability and in an ARE-luciferase reporter gene assay for Nrf2 modulation using HEK293 human embryonic kidney cells. Our findings indicate that, in contrast to cytotoxic methyl esters 1 and 2, the primary amides 3 and 4 activate the Nrf2 pathway at noncytotoxic concentrations. Overall, our data suggest that the anaenamide scaffold is tunable to produce differential biological outcomes.

Discovery, Total Synthesis, and SAR of Anaenamides A and B: Anticancer Cyanobacterial Depsipeptides with a Chlorinated Pharmacophore.

New modified depsipeptides and geometric isomers, termed anaenamides A (1a) and B (1b), along with the presumptive biosynthetic intermediate, anaenoic acid (2), were discovered from a marine cyanobacterium from Guam. Structures were confirmed by total synthesis. The alkylsalicylic acid fragment and the C-terminal α-chlorinated α,ß-unsaturated ester are novelties in cyanobacterial natural products. Cancer cell viability assays indicated that the C-terminal unit serves as the pharmacophore and that the double-bond geometry impacts the cytotoxicity.