Incorporation of ortho-carbaboranyl-Nε-modified L-lysine into neuropeptide Y receptor Y1- and Y2-selective analogues

J Med Chem. 2011 Apr 14;54(7):2368-77. doi: 10.1021/jm101514m. Epub 2011 Mar 11.

Abstract

Nontoxic ortho-carbaborane is one of the most promising structure for boron neutron capture therapy (BNCT). For directed uptake of ortho-carbaborane by tumor cells, receptor-subtype selective neuropeptide Y (NPY) and its derivatives were modified with ortho-carbaborane. The derivative [F(7), P(34)]-NPY has been shown to be a breast cancer selective ligand that binds to the Y(1)-receptor subtype, whereas [Ahx(5-24)]-NPY selectively addresses Y(2)-receptor subtypes that are found in neuroblastoma cells. ortho-Carbaboranyl propionic acid was synthesized and linked to the ε-amino group of N(α)-Fmoc protected L-lysine. The characterization of the compounds was performed by NMR, IR, and MS studies. The carbaborane-modified amino acid was incorporated into NPY, [F(7), P(34)]-NPY, and [Ahx(5-24)]-NPY by an optimized solid phase peptide synthesis using Fmoc protection. Binding studies and IP accumulation assays confirmed nanomolar affinity and activity of the modified analogues despite of the large carbaborane cluster. Internalization studies revealed excellent and receptor subtype specific uptake of the conjugates into respective cells.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Boranes / chemistry*
  • COS Cells
  • Chlorocebus aethiops
  • Drug Carriers / chemistry
  • Drug Carriers / metabolism
  • HEK293 Cells
  • Humans
  • Lysine / chemistry*
  • Lysine / metabolism*
  • Molecular Sequence Data
  • Protein Binding
  • Protein Transport
  • Receptors, Neuropeptide Y / chemistry*
  • Receptors, Neuropeptide Y / metabolism*
  • Substrate Specificity

Substances

  • Boranes
  • Drug Carriers
  • Receptors, Neuropeptide Y
  • neuropeptide Y-Y1 receptor
  • neuropeptide Y2 receptor
  • Lysine