Tutuilamides A-C: Vinyl-Chloride-Containing Cyclodepsipeptides from Marine Cyanobacteria with Potent Elastase Inhibitory Properties

ACS Chem Biol. 2020 Mar 20;15(3):751-757. doi: 10.1021/acschembio.9b00992. Epub 2020 Jan 28.


Marine cyanobacteria (blue-green algae) have been shown to possess an enormous capacity to produce structurally diverse natural products that exhibit a broad spectrum of potent biological activities, including cytotoxic, antifungal, antiparasitic, antiviral, and antibacterial activities. Using mass-spectrometry-guided fractionation together with molecular networking, cyanobacterial field collections from American Samoa and Palmyra Atoll yielded three new cyclic peptides, tutuilamides A-C. Their structures were established by spectroscopic techniques including 1D and 2D NMR, HR-MS, and chemical derivatization. Structure elucidation was facilitated by employing advanced NMR techniques including nonuniform sampling in combination with the 1,1-ADEQUATE experiment. These cyclic peptides are characterized by the presence of several unusual residues including 3-amino-6-hydroxy-2-piperidone and 2-amino-2-butenoic acid, together with a novel vinyl chloride-containing residue. Tutuilamides A-C show potent elastase inhibitory activity together with moderate potency in H-460 lung cancer cell cytotoxicity assays. The binding mode to elastase was analyzed by X-ray crystallography revealing a reversible binding mode similar to the natural product lyngbyastatin 7. The presence of an additional hydrogen bond with the amino acid backbone of the flexible side chain of tutuilamide A, compared to lyngbyastatin 7, facilitates its stabilization in the elastase binding pocket and possibly explains its enhanced inhibitory potency.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemistry
  • Aminobutyrates / chemistry
  • Antineoplastic Agents / isolation & purification*
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Chromatography, High Pressure Liquid
  • Cyanobacteria / chemistry*
  • Depsipeptides / chemistry
  • Depsipeptides / isolation & purification*
  • Depsipeptides / pharmacology
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / isolation & purification*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Lung Neoplasms / drug therapy*
  • Models, Molecular
  • Molecular Structure
  • Pancreatic Elastase / antagonists & inhibitors*
  • Peptides, Cyclic / isolation & purification*
  • Peptides, Cyclic / pharmacology
  • Piperidones / chemistry
  • Protein Binding
  • Tandem Mass Spectrometry
  • Vinyl Chloride / chemistry


  • 2-amino-2-butenoic acid
  • 3-amino-6-hydroxy-2-piperidone
  • Amino Acids
  • Aminobutyrates
  • Antineoplastic Agents
  • Depsipeptides
  • Enzyme Inhibitors
  • Peptides, Cyclic
  • Piperidones
  • lyngbyastatin 7
  • tutuilamide a
  • Pancreatic Elastase
  • Vinyl Chloride