CYCLIC RGD PEPTIDES CONTAINING BETA-TURN MIMETICS

The alpha(v) beta(3)-receptor, one member of the integrin family, is i mplicated in angiogenesis and in human tumor metastasis. Spatial scree ning led to the highly active first-generation peptide c(RGDfV), which shows a beta II'/gamma-turn arrangement with D-Phe in the i + 1 posit ion of the beta II'-turn. Further reduction of the flexibility should be achieved by incorporating different rigid building blocks (turn mim etics) like the (S)- and (R)-Gly[ANC-2]Leu dipeptide, the P-turn dipep tide (BTD) and the (S,S)-spiro-Pro-Leu moiety. These distinct beta-tur n mimetics are introduced by replacing the D-Phe-Val dipeptide in the lead structure c(RGDfV). In peptide analogues c(RGD''S-ANC'') (PA1), c (RGD''R-ANC'') (PA2), and c(RGD''BTD'') (PA3) the turn mimetic does no t adopt the desired position in the beta-turn, instead Gly occupies th e i + I position of the beta II'-turn, only c(RGD''spiro'') PA4 led to the desired beta II'/gamma-turn arrangement with the turn motif in th e i + 1 and i + 2 position of the beta-turn. These effects may arise f rom particular steric effects of the cyclic pentapeptide system in com bination with steric requirements of the ANC and BTD moiety. Additiona l investigations on cyclic hexapeptide derivatives show that the BTD o ccupies the expected i + 1 and i + 2 position of a beta II'-turn in th ese systems. Structure-activity investigations showed that the incorpo ration of the rigid turn motifs could not reduce the flexibility of th e RGD site (ANC and BTD) or fix a conformation which is unable to matc h the receptor very well (spiro). On the other hand, recent findings t hat the proton of the amide bond between Asp and the following amino a cid is essential for high activity can be confirmed. Moreover, the syn thesis of c(RGD''R-ANC'') PA2 led to one of the compounds most active in inhibiting vitronectin binding to the alpha(v) beta(3)-integrin.