Discovery of Bioactive Marine Natural Products

Approximately half of all current drugs are derived from natural products, demonstrating their potential for drug discovery. The structural diversity and biological activity displayed by natural products may be attributed to a long evolutionary selection process. In our quest for small molecules with biomedical utility for various disease indications we mainly investigate natural products. In particular, largely unexplored marine organisms such as marine cyanobacteria are evaluated as sources of bioactive secondary metabolites. A variety of phenotypic and target-based assays is being implemented in an evolving screening program. Active compounds are isolated using bioassay- or NMR-guided fractionation and their structures determined using a combination of spectroscopic techniques, predominantly NMR. For example, we have discovered potent elastase inhibitors (lyngbyastatins 4–10) and a potent class I histone deacetylase (HDAC) inhibitor (largazole), which have potential application in tissue injury diseases and cancer, respectively, among other indications. Grassystatins A–C could prove to be valuable novel probes for the study of cathepsin E function since they potently inhibit this enzyme with substantial selectivity over cathepsin D.

DiscoveryBioactive_Structures

Selected bioactive compounds from marine cyanobacteria discovered in the Luesch lab

Additionally, we are currently pursuing bioactive compounds with antiviral, antibacterial, antimalarial, antiinflammatory, immunomodulatory, neuroprotective and quorum-sensing inhibitory properties.

Sample Publications:

Taori, K.; Paul, V. J.; Luesch, H. “Structure and Activity of Largazole, a Potent Antiproliferative Agent from the Floridian Marine Cyanobacterium Symploca sp.” J. Am. Chem. Soc. 2008, 130, 1806–1807.

Kwan, J. C.; Rocca, J. R.; Abboud, K. A.; Paul, V. J.; Luesch, H. “Total Structure Determination of Grassypeptolide, a New Marine Cyanobacterial Cytotoxin” Org. Lett. 2008, 10, 789–792.

Taori, K.; Liu, Y.; Paul, V. J.; Luesch, H. “Combinatorial Strategies by Marine Cyanobacteria: Symplostatin 4, an Antimitotic Natural Dolastatin 10/15 Hybrid that Synergizes with the Coproduced HDAC Inhibitor Largazole” ChemBioChem 2009, 10, 1634–1639.

Kwan, J. C.; Eksioglu, E. A.; Liu, C.; Paul, V. J.; Luesch, H. “Grassystatins A–C from Marine Cyanobacteria, Potent Cathepsin E Inhibitors That Reduce Antigen Presentation” J. Med. Chem. 2009, 52, 5732–5747.

Matthew, S.; Salvador, L. A.; Schupp, P. J.; Paul, V. J.; Luesch, H. “Cytotoxic Halogenated Macrolides and Modified Peptides from the Apratoxin-Producing Cyanobacterium Lyngbya bouillonii from Guam” J. Nat. Prod. 2010, 73, 1544–1552.

Kwan, J. C.; Meickle, T.; Ladwa, D.; Teplitski, M.; Paul, V.; Luesch, H. “Lyngbyoic Acid, a ‘Tagged’ Fatty Acid from a Marine Cyanobacterium, Disrupts Quorum Sensing in Pseudomonas aeruginosaMol. BioSyst. 2011, 7, 1205‒1216.

 
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