Bioactive natural products from marine cyanobacteria: new structures and modes of action

Extracts of marine cyanobacteria show a high hit rate in our phenotypic assays for cancer cell toxicity and in target-based assays against various proteases. Our bioassay-guided fractionation resulted in the isolation of unusual, modified depsipeptides. Structures and activities that have resulted from our recent natural products based drug discovery efforts are presented. These include a new highly cytotoxic analogue of apratoxin A [1], the moderately cytotoxic grassypeptolide [2], the cancer cell selective largazole [3], and the elastase inhibitors lyngbyastatins 4–7 [4,5]. The lack of general strategies to elucidate modes of small molecule action identified in phenotypic assays prompted us to develop and apply unbiased global genomic approaches to target identification problems. Genome-wide approaches in yeast have proven useful to infer targets and target pathways of small molecules. These approaches are being systematically transferred into mammalian culture systems in order to interrogate more complex pathways, in a more relevant setting [6]. The current status of our mode of action studies on apratoxin A is discussed, which were initiated with gene dosage screens for drug susceptibility [7]. For other natural products, structure-based approaches resulted in the discovery of their targets.

Acknowledgements: Florida Sea Grant College Program, Grant No. NA06OAR4170014; James & Esther King Biomedical Research Program, Grant No. 06-NIR07.

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