Planta Med 2013; 79 - PC6
DOI: 10.1055/s-0033-1348562

Structure Activity Relationships of the Bioactive Lyngbyamide Class of Marine Natural Product

E Mevers 1, B Miller 1, 2, V Hook 2, WH Gerwick 1, 2
  • 1Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography University of California San Diego, La Jolla, California 92093, United States
  • 2Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093, United States

Alkyl amides are a growing class of marine natural products that have both physiological and pharmacological importance. In recent years, several alkyl amides (serinolamide, lyngbyamides and kimbeamides) have been isolated from marine cyanobacteria that exhibit a broad range of biological activity, including ion channel modulation, brine shrimp toxicity and cannabinoid receptor binding ability. This potential, coupled with the relative synthetic tractability of these alkyl amides, led to the design of a structure-activity relationship study of the lyngbyamides. The first round of synthetic analogs consisted of 36 different compounds, designed to probe the importance of several structural characteristics of the lyngbyamides. These compounds were tested in a wide array of biological assays, including cancer cell cytotoxicity, ion modulation, neuro-receptor binding, cathepsin L modulation and brine shrimp toxicity. Several interesting trends were seen between the structures and their activity, with one interesting finding being that those possessing a tertiary amide were strongly activating of cathepsin L-mediated proteolysis. Activation of cathepsin L may be of relevance for reducing tumor progression and aortic aneurysms, since deficiency of cathepsin L promotes tumor progression and is essential for abdominal aortic aneurysms in mice. To date there are no reports of any other marine natural product or analog that possesses this intriguing activity. Currently, two additional rounds of synthetic derivatives have been designed and synthesized to further probe this intriguing cathepsin L activation.