Stereoselective Synthesis of [L-Arg, L/D-3-(2-Naphthyl)alanine]-type (E)-Alkene Dipeptide Isosteres and Its Application to the Development of Peptidomimetic Analogs of the CXCR4 Antagonist FC131

Abstract

L,L- And L,D-type (E)-alkene dipeptide isosteres (EADIs), which have unnatural side chains at the α-position, were synthesized by the combination of stereoselective aziridinyl ring-opening reactions and organozinc-copper-mediated anti-SN2'reactions to a single substrate of γ,δ-cis-γ,δ-epimino (E)-α,β-enoate. The utility of this procedure was demonstrated by the stereo-controlled synthesis of a couple of diastereomeric EADIs of Arg-L/D-3-(2-naphthyl)alanine (Nal) that is contained in a low molecular weight CXCR4 antagonist FC131 [cyclo(-D-Tyr-Arg-Arg-Nal-Gly-)]. Several FC131 analogs, in which these EADIs were inserted for reduction of their peptide character, were synthesized for the development of nonpeptide CXCR4 antagonists with anti-HIV and anti-cancer-metastasis activity.

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