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.