Investigation of a Symploca sp. from Papua New Guinea has led to the isolation of symplocamide A (1), a potent cancer cell cytotoxin, which also inhibits serine proteases with a 200-fold greater inhibition of chymotrypsin over trypsin. The complete stereostructure of symplocamide A was determined by detailed NMR and MS analysis as well as chiral HPLC analysis of the component amino acid residues. The presence of several unusual structural features in symplocamide A provides new insights into the pharmacophore model for protease selectivity in this drug class and may underlie the potent cytotoxicity of this compound to H-460 lung cancer cells (IC 50 = 40 nM) as well as neuro-2a neuroblastoma cells (IC 50 = 29 nM).Marine cyanobacteria are a continuing source of many novel natural product structures, some of which possess highly potent biological properties. 1 Most of these metabolites are partially composed of amino acids, and these are often integrated with polyketide sections to make a wide range of nitrogen-rich lipids. These lipopeptide backbones are often modified by oxidation, methylation, or various halogenations, including those catalyzed by the recently described radical halogenases. 2,3 There is a growing body of literature that supports the hypothesis that the presence of halogen atoms in natural products enhances their biological potency. 4,5 Hence, we have been interested in isolating new types of halogenated lipopeptides from marine cyanobacteria with the goals of further defining the extent of their structural diversity and biological properties.Proteases are implicated in the pathogenesis of many human diseases, including cancer and Alzheimer's, and thus the therapeutic modulation of proteolytic activity offers an attractive potential treatment modality. Indeed, it has been estimated that of the approximately 400 human *To whom correspondence should be addressed. Tel: (858) 6 In addition, proteases from infectious pathogens such as HIV, HCV, and dengue virus are crucial drug targets for the improvement of human health. However, with this multitude of different proteases and many potential therapeutic applications, discovery of agents with selectivity for specific proteases is crucial to the development of truly useful pharmaceuticals in this class.While freshwater cyanobacteria are a rich source of structurally diverse protease inhibitors, 7 their marine relatives represent an under-explored resource of this enzyme-inhibitor class. Hence, we have initiated a program to survey marine cyanobacterial extracts, fractions, and newly isolated pure compounds for interesting profiles of protease inhibition. This line of research has been productive and led to the identification of the depsipeptide symplocamide A (1), which shows strong serine protease inhibitory activity. In addition, symplocamide A shows a high level of cytotoxicity to cancer cells in vitro (H-460 lung cancer cells, IC 50 = 40 nM; neuro-2a neuroblastoma cells, IC 50 = 29 nM). These biological properties combined with its unusual s...

No abstract

Cancer cell toxicity-guided fractionation of extracts of the Papua New Guinea marine cyanobacteria Lyngbya majuscula and Lyngbya sordida led to the isolation of apratoxin D (1). Compound 1 contains the same macrocycle as apratoxins A and C but possesses the novel 3,7-dihydroxy-2,5,8,10,10-pentamethylundecanoic acid as the polyketide moiety. The planar structures and stereostructures of compound 1 were determined by extensive 1D and 2D NMR and MS data analyses and by comparison with the spectroscopic data of apratoxins A and C. Apratoxin D (1) showed potent in vitro cytotoxicity against H-460 human lung cancer cells with an IC 50 value of 2.6 nM.