SYNTHESIS OF 13H-BENZO[6,7]INDOLO[3,2-C]QUINOLINES AND 13H-BENZO[4,5]INDOLO[3,2-C]QUINOLINES - A NEW SERIES OF POTENT SPECIFIC LIGANDS FOR TRIPLEX DNA

Triple-helical complexes formed upon binding of oligonucleotides to ol igopyrimidine oligopurine sequences of double-helical DNA can be stabi lized by intercalating ligands such as benzopyridoindole derivatives ( Mergny et al. Science 1992, 256, 1681). Based on molecular modeling st udies, it was predicted that better stacking interactions could be ach ieved between the intercalator and base triplets by extending the size of the aromatic ring system. Here we describe the synthesis of pentac yclic aromatic molecules which exhibit a highly selective binding to t ripler structures. The thermal Fischer indolization of hydrazones resu lting from 4-hydrazinoquinolin-2(1H)-one and 6-methoxy-1 (and -2)-tetr alones led to the expected cyclized intermediates. After complete arom atization, 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 d iamines provided derivatives of these pentacyclic ring systems which a re, so far, the most potent DNA tripler-specific ligands ever describe d in our studies.