DNA intercalating compounds as potential antitumor agents. 2. Preparation and properties of 7H-pyridocarbazole dimers

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Abstract
To obtain antitumor agents, various 7H-pyridocarbazole dimers were prepared by quaternization of the pyridinic N of the different isomeric 7H-pyridocarbazole rings with halogenoamino alicyclic or aliphatic chains. The dimers interact with DNA more markedly than with the corresponding monomer; the bisintercalation depends upon the nature, the flexibility and the ionization state of the linking chains. They most often bisintercalate at pH 5 where the chain is protonated and monointercalate at pH 7.4. The apparent binding constants (Kap) range from 108 to 10 9 M-1 at pH 5 and from 5 .times. 105 to 2 .times. 107 M-1 at pH 7.4. The bisintercalating dimers covered 4 DNA base pair; most of the monointercalating dimers covered 2 bases pairs. The antitumor activity against L1210 murine leukemia cells is strongly dependent on the position of attachment, the nature of the linking chain and its rigidity. Three highly active dimers were obtained in the series of 7H-pyridol[4,3-c]carbazole dimers with rigid bis(ethylpiperidinyl) chains. Two ellipticine dimers were prepared which were found completely inactive on L1210. In the series of 7H-pyridocarbazoles the process of dimerization apparently leads to very active antitumor compounds.