Synthesis of Cyclopeptidic Analogues of Triostin A with Quinoxalines or Nucleobases as Chromophores

摘要

The natural antibiotic triostin A (1) is based on a conforma-tionally rigid disulfide-bridged cyclo-octadepsipeptide scaffold.This bicyclic core structure provides a perfect preorgan-ization of two covalently attached quinoxalines resulting in sequence-specific bis(intercalation) of the chromophores in double-stranded DNA.Herein for the first time the corresponding cyclopeptide has been synthesized as a scaffold instead of the cyclodepsipeptide of triostin A by solid-phase peptide synthesis followed by bis(cyclization) in solution.Furthermore,when in contact with DNA the bicyclic peptide provides additional hydrogen-bonding possibilities and greater conformational rigidity in comparison to triostin A.These modifications to the backbone of triostin A might be especially valuable in combination with the use of nucleo-bases instead of quinoxalines for additional DNA recognition next to bis (intercalation) like major groove binding or detection of abasic DNA damages.