engleski

Cyclic Enediyne-Amino Acid Chimeras as New Aminopeptidase N Inhibitors

Enediyne-peptide conjugates were designed with the aim to inhibit aminopeptidase N, a widespread ectoenzyme with a variety of functions, like protein digestion, inactivation of cytokines in the immune system and endogenous opioid peptides in the central nervous system. Enediyne moiety was embedded within the 12-membered ring with hydrophobic amino acid alanine, valine, leucine or phenylalanine used as carriers. Aromatic part of the enediyne bridging unit and the amino acid side-chains were considered pharmacophores for the binding to the APN active site. Additionally, the fused enediyne-amino acid "heads" were bound through a flexible linker to the L-lysine, an amino group donor. The synthesis included building the aromatic enediyne core at the C-terminal of amino acids and subsequent intramolecular N- alkylation. APN inhibition test revealed that the alanine-based derivative 9a inhibits the APN with IC50 of 34 ± 11 M. Enediyne-alanine conjugate 12 missing the flexible linker was much less effective in the APN inhibition. These results show that enediyne-fused amino acids have potential as new pharmacophores in the design of APN inhibitors.

aminopeptidase N; enediyne-peptide conjugate; enzyme inhibitors; amino acids

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