Chloroalkene dipeptide isosteres as peptidomimetics

Abstract

To date various biologically active peptides have been discovered, characterized and modified for drug discovery. However, the utilization of peptides as therapeutics involves some limitation due to several factors, including low metabolic stability owing to proteolysis and non-specific interactions with multiple off-target molecules. Hence, the development of "peptidomimetics," in which a part or whole of a molecule is modified, is a desirable strategy to enhance the stability or bioactivity of peptide-based drugs. In this situation, we have designed and developed a synthetic method for chloroalkene dipeptide isosteres (CADIs), which involves replacement of an amide bond in peptides with a chloroalkene structure and are classified as peptidomimetics. By a developed synthetic method, an N-tert-butylsulfonyl protected CADI can be obtained utilizing diastereoselective allylic alkylation with organocopper reagents as a key reaction. This CADI can be transformed into an N-fluorenylmethoxycarbonyl protected CADI in short steps. In addition, CADIs are used in Fmoc-based solid-phase peptide synthesis and introduced into a bioactive peptide. Protocols for practical preparation of some CADIs and peptide mimetics containing a CADI are described as detailed recipes.

Keywords: Alkene-type dipeptide isostere; Chloroalkene dipeptide isostere; Cyclic RGD peptide; Diastereoselective 1,4-asymmetric induction; Integrin; Organocopper reagent; Organozinc reagent; Peptide-lead drug; Peptidomimetic; Solid-phase peptide synthesis.