Modulation of the antitumor activity by methyl substitutions in the series of 7H-pyridocarbazole monomers and dimers.

The structure of the dimeric antitumor drug ditercalinium (NSC 366241) [2,2'-([4,4'-bipiperidine]-1,1'-diyldi-2,1-ethanediyl)bis[10 -methoxy-7H-pyrido[4,3-c]carbazolium] tetramethanesulfonate] was modified by introduction of methyl groups in various positions of the aromatic ring. Monomeric analogues with the nitrogen atom of the pyridinic ring in different positions have also been synthesized. Pharmacological properties and DNA interactions of the new compounds are reported. In contrast with the monomeric analogue of ditercalinium, which was inactive, methyl substitutions on the 10-methoxy-7H-pyrido[4,3-c]carbazolium in positions 6 or 7 led to monomers endowed with small but significant activity. As expected, dimerization of the methyl-substituted pyridocarbazoles yielded DNA bisintercalators with affinity slightly higher than that of the unsubstituted parent compounds. These dimers, characterized by a relatively better therapeutic index, have the same mechanism of action as ditercalinium. Otherwise, in monomeric and dimeric series, methyl substitution in position 4 or 5 provided inactive compounds unable to intercalate into DNA. All these results are in agreement with the previously proposed geometry for the complex of ditercalinium with DNA.