期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 21, 期 12, 页码 3582-3589出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2013.02.051
关键词
Proximicin; Structural conformation; DFT calculations; DNA binding; gamma-Peptide
资金
- Deutsche Forschungsgemeinschaft (DFG) [SU 239-5/1]
- Cluster of Excellence 'Unifying Concepts in Catalysis'
- DFG
- Conseil Regional du Limousin
- COST action [CM0804]
- Operational Program Research and Development for Innovations-European Regional Development Fund (Ministry of Education, Youth and Sports of the Czech Republic) [CZ.1.05/2.1.00/03.0058]
The proximicins A-C are naturally occurring cytotoxic c-peptides that contain the unique 4-amino-furan-carboxylic acid. In contrast to the structurally related cytotoxic natural DNA binder netropsin and distamycin, both exhibiting as core building block N-methyl-4-amino-pyrrol-carboxylic acid, no DNA binding was observed for the procimicins. X-ray analysis of crystals of a protected 4-amino-furan-2-carboxylic acid dipeptide revealed a stretched conformation. In contrast, for netropsin and distamycin, sickle-shaped crystal conformations were observed. DFT-calculations elegantly confirm these conformational arrangements. The most stable conformers of the proximicins are linear whereas sickle-shaped conformations are less stable, having higher Gibbs energies. For netropsin, distamycin and the netropsin-proximicin-hybrid a sickle shaped conformation appears energetically favored. The reported results are consistent with the observations that the proximicins A-C do not bind to the DNA and have a different mode of action concerning their cytotoxic activity with respect to netropsin and distamycin. (C) 2013 Elsevier Ltd. All rights reserved.
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