On-line synthesis of pseudopeptide library incorporating a benzodiazepinone turn mimic: biological evaluation on MC1 receptors

J Comb Chem. 2007 Mar-Apr;9(2):254-62. doi: 10.1021/cc060054q.

Abstract

Alpha melanocyte stimulating hormone (alpha-MSH) is a widely distributed hormone. This tridecapeptide exhibits various biological activities mediated through different receptors. alpha-MSH binds to the melanocortin-1 receptor (MC1-R), mainly expressed in keratinocytes and melanocytes, inducing melanogenesis and anti-inflammatory processes. The central His-Phe-Arg-Trp tetrapeptide sequence of alpha-MSH is known to form a turn in the bioactive conformation. To find new potent analogs of alpha-MSH, we decided to introduce non-peptide building blocks in the alpha-MSH sequence. Molecular modeling studies showed that two amino acids of the central core sequence could be replaced by the benzodiazepinone building block without loosing the beta-turn conformation. Benzodiazepines are well-known pharmacophores exhibiting a wide scope of biological activities and are described as constrained dipeptide mimics templates. Although numerous synthetic pathways leading to benzodiazepinones have been described in literature, no methodology has 1,4-benzodiazepine-2,5-diones building blocks bearing a free carboxylic acid function and a protected amino function suitable for incorporation into peptide sequences. In this study, we report the synthesis of peptides with a benzodiazepinone moiety obtained directly during the course of solid-phase peptide synthesis (SPPS). This "on-line" strategy leads to the generation of a 54-member pseudo-peptide library of alpha-MSH analogs. After LC/MS purification, binding assays were performed on the MC1 receptor leading to the discovery of several micromolar ligands.

MeSH terms

  • Benzodiazepinones / chemical synthesis
  • Benzodiazepinones / pharmacology*
  • Cells, Cultured
  • Humans
  • Models, Molecular
  • Molecular Mimicry*
  • Peptides / chemical synthesis*
  • Receptor, Melanocortin, Type 1 / drug effects*

Substances

  • Benzodiazepinones
  • Peptides
  • Receptor, Melanocortin, Type 1