The synthesis of alternative diketopiperazines as potential RGD mimetics (original) (raw)

2006, Journal of Peptide Science

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 µM value. On the other hand only 3 binds with measurable activity to the α IIb β 3 receptor (IC 50 159 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. Molecular geometry optimizations were performed in the case of c(Arg-Asp), c(Arg-Glu) and c[Arg-Asp(Phe-OH)] at RAM1 level of theory using Gaussian03 [4]. The highest possible fixed distance values were used for each peptide. c[Arg(Tos)-Glu(OMe)]. 1 H NMR: δ 8.16 (2H, s, lactam NHs), 7.62 and 7.28 (2x2H, d, J = 7.2 Hz, ArHs in Tos), 7.03, 6.73 and 6.56 (3x1H, 3xbr s, guanidino NHs), 3.86 [1H, t, J = 5.1 Hz, α-CH (Glu)], 3.80 [1H, t, J = 4.8 Hz, α-CH (Arg)], Figure 4 Inhibition of binding of fibronectin to isolated α IIb β 3 integrin receptor with c(Arg-Asp); c(Arg-Glu) and c[Arg-Asp(Phe-OH)] IC 50 159 µM.