Incorporation of the unusual C(alpha)-fluoroalkylamino acids into cyclopeptides: synthesis of arginine-glycine-aspartate (RGD) analogues and study of their conformational and biological behavior

Journal of Medicinal Chemistry
Alma Dal PozzoGiuseppe Giannini

Abstract

A series of six arginine-glycine-aspartate (RGD) cyclopeptide analogues containing a C(alpha)-di- or trifluoromethylamino acid (alpha-Dfm or alpha-TfmAaa) at different positions of the ring were synthesized. All peptides were obtained in two diastereomeric forms, which were separated by HPLC. In vitro biological tests of the new cyclopeptides P were carried out in comparison with their corresponding cyclopeptides R lacking the alpha-fluoromethyl group. Five out of the six compounds P-I (containing (S)-alpha-Tfm-Aaa) showed activities in the nanomolar range, while the P-II compounds (containing (R)-alpha-Tfm-Aaa) were much less active or totally inactive. Only cyclo[RGDf-(S)-alphaTfmV] (P1-I) was found to be significantly more active than its model compound cyclo(RGDfV) (R1). The three-dimensional structure in water and DMSO was determined by NMR techniques and molecular dynamics (MD) calculations, but it was not possible to highlight significant differences in the backbone conformation of the peptides examined. Significant interproton distances, derived from nuclear Overhauser effect (NOE) experiments, were used to determine the absolute configuration of the side chains.

References

Jul 11, 2000·The Journal of Peptide Research : Official Journal of the American Peptide Society·A Dal PozzoS Colli
Feb 22, 2002·Journal of Medicinal Chemistry·Simon L GoodmanHorst Kessler
Nov 16, 2002·Angewandte Chemie·Micha JostNorbert Sewald
Oct 3, 2003·Journal of Medicinal Chemistry·Luciana MarinelliHorst Kessler
Aug 6, 2004·Journal of Medicinal Chemistry·Luciana MarinelliHorst Kessler

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Citations

May 24, 2017·Organic Letters·Amber A S Gietter-BurchDonald A Watson

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