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 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.