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The synthesis of alternative diketopiperazines as potential RGD mimetics
Author(s) -
Mihala Nikolett,
Csámpai Antal,
Ilaš Janez,
Kikelj Danijel,
Kiss Robert,
SüliVargha Helga
Publication year - 2006
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.776
Subject(s) - chemistry , diketopiperazines , derivatization , stereochemistry , peptide , peptide synthesis , arginine , glycine , combinatorial chemistry , ic50 , methanol , protecting group , amino acid , organic chemistry , biochemistry , alkyl , high performance liquid chromatography , in vitro
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 β‐ t ‐butyl or β‐cyclohexyl esters are stable under the same conditions. In spite of the simple structure, all compounds bind selectively to the α v β 3 integrin receptor, 3 showing the highest affinity with an IC 50 value of 0.74 µ M value. On the other hand only 3 binds with measurable activity to the α IIb β 3 receptor (IC 50 159 µ M ). 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. Copyright © 2006 European Peptide Society and John Wiley & Sons, Ltd.