Cyclo(-arginyl-sarcosyl-aspartyl-phenylglycyl-)2. Simple synthesis of an RGD-related peptide with inhibitory activity for platelet aggregation

Abstract

The dimerization–cleavage of the tetrapeptide precursor bound to the benzophenone oxime resin afforded cyclo[-Arg(Tos)-Sar-Asp(OcHex)-Phg-]₂, a cyclic analogue of the RGD peptide. The yield and the selectivity between the tetra-/octa-peptide formed through the cyclization–cleavage depended on the sequence of the tetrapeptide. The ratio of tetra-/octa-peptide also depended on the substitution level of the oxime resin with the peptide segment. The cyclic octapeptide was also synthesized through the solution-phase dimerization–cyclization from the linear tetrapeptide precursor. The solution-phase dimerization–cyclization was very efficiently mediated with BOP/HOBt as the condensation reagent. ¹H NMR and CD spectra suggested that the cyclic octapeptide was of some restricted conformation, which might be involved in the preferred formation of the octapeptide in both solid- and solution-phase syntheses. The octapeptide showed potent inhibitory activity toward platelet aggregation; however, it showed no activity toward cell adhesion.