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 (<b>3)</b> and D (<b>4</b>). These compounds were isolated from a novel <i>Hormoscilla</i> 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 (<i>Hormoscilla</i> sp.), and other previously documented species of the genus <i>Hormoscilla</i>. The planar structures of <b>3</b> and <b>4</b> 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 <b>1</b> and <b>2</b> to generate anaenoic acid (<b>7</b>), which served as a point for diversification, providing the primary amides <b>3</b> and <b>4</b> from synthetic intermediates <b>5</b> and <b>6</b>, 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 <b>1</b> and <b>2</b>, the primary amides <b>3</b> and <b>4</b> activate the Nrf2 pathway at noncytotoxic concentrations. Overall, our data suggest that the anaenamide scaffold is tunable to produce differential biological outcomes.