The synthesis of alternative diketopiperazines as potential RGD mimetics.
Alternative RGD mimetics-with the exception of glycine-c(Arg-Asp) 1, c(Arg-Glu) 2 and c[Arg-Asp(Phe-OH)] 3 were synthesized. The DKPs were prepared on solid phase with orthogonal protection allowing further derivatization in solution. During solution phase cyclization in NH(3)/methanol, the side chain benzyl ester group of H-Arg(Tos)-Asp(OBzl)-OMe and H-Arg(Tos)-Glu(OBzl)-OMe suffer transesterification, while beta-t-butyl or beta-cyclohexyl esters are stable under the same conditions. In spite of the simple structure, all compounds bind selectively to the alpha(v)beta(3) integrin receptor, 3 showing the highest affinity with an IC(50) value of 0.74 microM value. On the other hand only 3 binds with measurable activity to the alpha(IIb)beta(3) receptor (IC(50) 159 microM). The binding affinities seem to be in accordance with the distances between the arginine guanidino and the aspartic acid carboxyl group in extended conformation determined by semiempirical geometry optimization.
Mihala
Nikolett
N
Research Group for Peptide Chemistry, Hungarian Academy of Sciences, Eötvös Loránd University, Budapest, Hungary.
Csámpai
Antal
A
Ilas
Janez
J
Kikelj
Danijel
D
Kiss
Robert
R
Süli-Vargha
Helga
H
D002625:Chemistry, Organic / Q000379:methods*; D054659:Diketopiperazines; D005340:Fibrinogen / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D016023:Integrins / Q000187:drug effects / Q000378:metabolism; D018716:Molecular Mimicry; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D010879:Piperazines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D019096:Vitronectin / Q000187:drug effects / Q000378:metabolism
D054659:Diketopiperazines; D016023:Integrins; D009842:Oligopeptides; D010879:Piperazines; D019096:Vitronectin; C047981:arginyl-glycyl-aspartic acid; D005340:Fibrinogen