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.
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.
Dal Pozzo
Alma
A
Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, Via G. Colombo 81, 20133 Milano, Italy. dalpozzo@ronzoni.it
Ni
Minghong
M
Muzi
Laura
L
de Castiglione
Roberto
R
Mondelli
Rosanna
R
Mazzini
Stefania
S
Penco
Sergio
S
Pisano
Claudio
C
Castorina
Massimo
M
Giannini
Giuseppe
G
D000596:Amino Acids / Q000737:chemistry*; D004121:Dimethyl Sulfoxide; D005461:Fluorine; D039302:Integrin alphaVbeta3 / Q000737:chemistry; D016023:Integrins / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D019030:Receptors, Vitronectin / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014867:Water
D000596:Amino Acids; D039302:Integrin alphaVbeta3; D016023:Integrins; D009842:Oligopeptides; D010456:Peptides, Cyclic; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; D014867:Water; D005461:Fluorine; C047981:arginyl-glycyl-aspartic acid; D004121:Dimethyl Sulfoxide