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 dolastatin 10 from marine cyanobacteria, an analogue of which (MMAE) is the payload of the FDA-approved antibody-drug conjugates brentuximab vedotin and polatuzumab vedotin for the treatment of certain lymphomas, and enfortumab vedotin for recurrent bladder cancer.  We identified the anticancer apratoxins that act as inhibitors of cotranslational translocation and isolated potent neutrophil elastase inhibitors (lyngbyastatins 4–10) with potential application to lung tissue injuries, as well as a potent class I histone deacetylase (HDAC) inhibitor (largazole) with application for cancer, bone disorders and other indications. 

Structures Dec. 2019 Luesch

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

Sample Publications:

  1. Liang, X.; Luo, D.; Yan, J.-L.; Rezaei, M. A.; Salvador-Reyes, L. A.; Gunasekera, S. P.; Li, C.; Ye, T.; Paul, V. J.; Luesch, H. “Discovery of Amantamide, a Selective CXCR7 Agonist from Marine Cyanobacteria” Org. Lett. 2019, 21, 1622–1626.
  2. Luo, D.; Putra, M. Y.; Ye, T.; Paul, V. J.; Luesch, H. “Isolation, Structure Elucidation and Biological Evaluation of Lagunamide D: A New Cytotoxic Macrocyclic Depsipeptide from Marine Cyanobacteria” Mar. Drugs 2019, 17, 83.
  3. Cai, W.; Salvador-Reyes, L. A.; Zhang, W.; Chen, Q.-Y.; Matthew, S.; Ratnayake, R.; Seo, S. J.; Dolles, S.; Gibson, D. J.; Paul, V. J.; Luesch, H. “Apratyramide, a Marine-Derived Peptidic Stimulator of VEGF-A and Other Growth Factors with Potential Application in Wound Healing” ACS Chem. Biol. 2018, 13, 91–99.
  4. Al-Awadhi, F. H.; Law, B. K.; Paul, V. J.; Luesch, H. “Grassystatins D–F, Potent Aspartic Protease Inhibitors from Marine Cyanobacteria as Potential Antimetastatic Agents Targeting Invasive Breast Cancer” J. Nat. Prod. 2017, 80, 2969–2986.
  5. Al-Awadhi, F. H.; Salvador, L. A. ; Law, B. K.; Paul, V. J.; Luesch, H. “Kempopeptin C, a Novel Marine-Derived Serine Protease Inhibitor Targeting Invasive Breast Cancer” Mar. Drugs 2017, 15, 290.
  6. Gunasekera, S. P.; Li, Y.; Ratnayake, R.; Luo, D.; Lo, J.; Reibenspies, J. H.; Xu, Z.; Clare-Salzler, M. J.; Ye, T.; Paul, V. J.; Luesch, H. “Discovery, Total Synthesis and Key Structural Elements for the Immunosuppressive Activity of Cocosolide, a Symmetrical Glycosylated Dimer from Marine Cyanobacteria” Chem. Eur. J. 2016, 22, 8158–8166.
  7. Salvador-Reyes, L. A.; Sneed, J.; Paul, V. J.; Luesch, H. “Amantelides A and B, Polyhydroxylated Macrolides with Differential Broad-Spectrum Cytotoxicity from a Guamanian Marine Cyanobacterium” J. Nat. Prod. 2015, 78, 1957–1962.
  8. 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.
  9. Kwan, J. C.; Ratnayake, R.; Abboud, K. A.; Paul, V. J.; Luesch, H. “Grassypeptolides A–C, Cytotoxic Bis-thiazoline Containing Marine Cyclodepsipeptides” J. Org. Chem. 2010, 75, 8012–8023.
  10. 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.
  11. Kwan, J. C.; Eksioglu, E. A.; Liu, C.; Paul, V. J.; Luesch, H. “Grassystatins A–C, Potent Cathepsin E Inhibitors That Reduce Antigen Presentation” J. Med. Chem. 2009, 52, 5732–5747.
  12. 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.
  13. 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.
  14. 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.
  15. Taori, K.; Matthew, S.; Rocca, J. R.; Paul, V. J.; Luesch, H. “Lyngbyastatins 5–7, Potent Elastase Inhibitors from Floridian Marine Cyanobacteria, Lyngbya spp.”  J. Nat. Prod. 2007, 70, 1593–1600.

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