Synthesis of 13<i>H</i>-Benzo[6,7]- and 13<i>H</i>-Benzo[4,5]indolo[3,2-<i>c</i>]- quinolines: A New Series of Potent Specific Ligands for Triplex DNA

Abstract

Triple-helical complexes formed upon binding of oligonucleotides to oligopyrimidine·oligopurine sequences of double-helical DNA can be stabilized by intercalating ligands such as benzopyridoindole derivatives (Mergny et al. Science 1992, 256, 1681). Based on molecular modeling studies, it was predicted that better stacking interactions could be achieved between the intercalator and base triplets by extending the size of the aromatic ring system. Here we describe the synthesis of pentacyclic aromatic molecules which exhibit a highly selective binding to triplex structures. The thermal Fischer indolization of hydrazones resulting from 4-hydrazinoquinolin-2(1H)-one and 6-methoxy-1 (and -2) -tetralones led to the expected cyclized intermediates. After complete aromatization, these compounds were transformed by phosphorus oxychloride giving 6-chloro-10-methoxy-13H-benzo[6,7]- (and 6-chloro-9-methoxy-13H-benzo[4,5]-) indolo[3,2-c]quinolines. Usual substitution by various diamines provided derivatives of these pentacyclic ring systems which are, so far, the most potent DNA triplex-specific ligands ever described in our studies.