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 NH3/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 αvβ3 integrin receptor, 3 showing the highest affinity with an IC50 value of 0.74 µM value. On the other hand only 3 binds with measurable activity to the αIIbβ3 receptor (IC50 159 µM). 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.

[1]  S. Andronati,et al.  Peptidomimetics - antagonists of the fibrinogen receptors: molecular design, structures, properties and therapeutic applications. , 2004, Current medicinal chemistry.

[2]  P. Fischer.  Diketopiperazines in peptide and combinatorial chemistry , 2003, Journal of peptide science : an official publication of the European Peptide Society.

[3]  Ralph Mazitschek,et al.  Synthesis and Biological Investigation of Novel Tricyclic Benzodiazepinedione‐Based RGD Analogues , 2002, Chembiochem : a European journal of chemical biology.

[4]  V. Ivanov,et al.  Cyclic dipeptides as building blocks for combinatorial libraries. Part 2: Synthesis of bifunctional diketopiperazines , 2002 .

[5]  D. Beshore,et al.  Recent advances in the synthesis of diketopiperazines , 2002 .

[6]  Thilo Stehle,et al.  Crystal Structure of the Extracellular Segment of Integrin αVβ3 in Complex with an Arg-Gly-Asp Ligand , 2002, Science.

[7]  Horst Kessler,et al.  Stereoisomeric Peptide Libraries and Peptidomimetics for Designing Selective Inhibitors of the αvβ3 Integrin for a New Cancer Therapy , 1997 .

[8]  E. Giralt,et al.  Diketopiperazine Formation in Solid Phase Peptide Synthesis Using p‐Alkoxybenzyl Ester Resins and FMOC‐Amino Acids. , 1986 .

[9]  Kenji. Suzuki,et al.  Acetic acid-catalyzed diketopiperazine synthesis. , 1981 .

[10]  J. Westley,et al.  Simple route to sterically pure diketopiperazines. , 1968, The Journal of organic chemistry.

[11]  E. Fischer.  Synthese von Polypeptiden. XV , 1906 .