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Tutuilamides A-C: Vinyl-Chloride-Containing Cyclodepsipeptides from Marine Cyanobacteria with Potent Elastase Inhibitory Properties.
- Source :
-
ACS chemical biology [ACS Chem Biol] 2020 Mar 20; Vol. 15 (3), pp. 751-757. Date of Electronic Publication: 2020 Jan 28. - Publication Year :
- 2020
-
Abstract
- 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.
- Subjects :
- Amino Acids chemistry
Aminobutyrates chemistry
Antineoplastic Agents pharmacology
Cell Line, Tumor
Cell Survival drug effects
Chromatography, High Pressure Liquid
Depsipeptides chemistry
Depsipeptides pharmacology
Drug Screening Assays, Antitumor
Enzyme Inhibitors pharmacology
Humans
Models, Molecular
Molecular Structure
Peptides, Cyclic pharmacology
Piperidones chemistry
Protein Binding
Tandem Mass Spectrometry
Vinyl Chloride chemistry
Antineoplastic Agents isolation & purification
Cyanobacteria chemistry
Depsipeptides isolation & purification
Enzyme Inhibitors isolation & purification
Lung Neoplasms drug therapy
Pancreatic Elastase antagonists & inhibitors
Peptides, Cyclic isolation & purification
Subjects
Details
- Language :
- English
- ISSN :
- 1554-8937
- Volume :
- 15
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- ACS chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 31935054
- Full Text :
- https://doi.org/10.1021/acschembio.9b00992