Targeting the Major Groove of the Palindromic d(GGCGCC) 2 Sequence by Oligopeptide Derivatives of Anthraquinone Intercalators.

GC-rich sequences are recurring motifs in oncogenes and retroviruses and could be targeted by noncovalent major-groove therapeutic ligands. We considered the palindromic sequence d(G 1 G 2 C 3 G 4 C 5 C 6 ) 2 , and designed several oligopeptide derivatives of the anticancer intercalator mitoxantrone. The stability of their complexes with an 18-mer oligonucleotide encompassing this sequence in its center was validated using polarizable molecular dynamics. We report the most salient structural features of two novel compounds, having a dialkylammonium group as a side chain on both arms. The anthraquinone ring is intercalated in the central d(CpG) 2 sequence with its long axis perpendicular to that of the two base pairs. On each strand, this enables each ammonium group to bind in-register to O 6 /N 7 of the two facing G bases upstream. We subsequently designed tris-intercalating derivatives, each dialkylammonium substituted with a connector to an N 9 -aminoacridine intercalator extending our target range from a six- to a ten-base-pair palindromic sequence, d(C 1 G 2 G 3 G 4 C 5 G 6 C 7 C 8 C 9 G 10 ) 2 . The structural features of the complex of the most promising derivative are reported. The present design strategy paves the way for designing intercalator-oligopeptide derivatives with even higher selectivity, targeting an increased number of DNA bases, going beyond ten.