Viequeamide A, a Cytotoxic Member of the Kulolide Superfamily of Cyclic Depsipeptides from a Marine Button Cyanobacterium

The viequeamides, a family of 2,2-dimethyl-3-hydroxy-7-octynoic acid (Dhoya)-containing cyclic depsipeptides, were isolated from a shallow subtidal collection of a “button” cyanobacterium (<i>Rivularia</i> sp.) from near the island of Vieques, Puerto Rico. Planar structures of the two major compounds, viequeamide A (<b>1</b>) and viequeamide B (<b>2</b>), were elucidated by 2D-NMR spectroscopy and mass spectrometry, whereas absolute configurations were determined by traditional hydrolysis, derivative formation, and chromatography in comparison with standards. In addition, a series of related minor metabolites, viequeamides C–F (<b>3</b>–<b>6</b>), were characterized by HRMS fragmentation methods. Viequeamide A was found to be highly toxic to H460 human lung cancer cells (IC₅₀ = 60 ± 10 nM), whereas the mixture of B–F was inactive. From a broader perspective, the viequeamides help to define a “superfamily” of related cyanobacterial natural products, the first of which to be discovered was kulolide. Within the kulolide superfamily, a wide variation in biological properties is observed, and the reported producing strains are also highly divergent, giving rise to several intriguing questions about structure–activity relationships and the evolutionary origins of this metabolite class