Conformationally Constrained Substance P Analogues: The Total Synthesis of a Constrained Peptidomimetic for the Phe7-Phe8 Region

Citations Over TimeTop 12% of 2000 papers

Abstract

A lactam-based peptidomimetic for the Phe7-Phe8 region of substance P has been synthesized. The synthesis used an anodic amide oxidation to selectively functionalize the C5-position of a 3-phenylproline derivative. The resulting proline derivative was coupled to a Cbz-protected phenylalanine, and an intramolecular reductive amination strategy used to convert the coupled material into a bicyclic piperazinone ring skeleton. The net result was a dipeptide building block that imbedded one of two proposed receptor bound conformations for the Phe7-Phe8 region of substance P into a bicyclic ring skeleton. The building block was then converted into a constrained substance P analogue with the use of solid-phase peptide synthesis. A similar intramolecular reductive amination strategy was used to synthesize a substance P analogue having only Phe7 constrained, and the original 3-phenylproline was converted into a substance P analogue having only Phe8 constrained. All of the analogues were examined for their ability to displace substance P from its NK-1 receptor.

Related Papers

• → Synthesis of a Chloroalkene Dipeptide Isostere-Containing Peptidomimetic and Its Biological Application(2017)21 cited
• → Development of Methods for Convergent Synthesis of Chloroalkene Dipeptide Isosteres and Its Application(2021)14 cited
• → Stereoselective synthesis of Gly-Gly-type (E)-methylalkene and (Z)-chloroalkene dipeptide isosteres and their application to 14-mer RGG peptidomimetics(2020)9 cited
• → Synthesis of a fluoroalkene peptidomimetic precursor of N-acetyl-l-glutamyl-l-alanine(2007)34 cited
• → Arg-Gly thiomethylene dipeptide surrogates: Synthesis and incorporation into Arg-Gly-Asp pseudotripeptides(1994)5 cited