DNA intercalating compounds as potential antitumor agents. 2. Preparation and properties of 7H-pyridocarbazole dimers.
In order to obtain antitumor agents, various 7H-pyridocarbazole dimers were prepared by quaternization of the pyridinic nitrogens of the different isomeric 7H-pyridocarbazole rings with halogenoamino alicyclic or aliphatic chains. The dimers interact with DNA more markedly than with the corresponding monomers, and 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 10(8) to 10(9) M-1 at pH 5 and from 5 X 10(5) to 2 X 10(7) M-1 at pH 7.4. The bisintercalating dimers covered four DNA base pairs, whereas most of the monointercalating dimers covered two bases pairs. The antitumor activity against L1210 murine leukemia 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-pyrido[4,3-c]carbazole dimers with rigid bis(ethylpiperidinyl) chains. On the other hand, two ellipticine dimers were prepared which were found completely inactive on L1210. These results show that in the series of 7H-pyridocarbazoles the process of dimerization leads to very active antitumor compounds.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D002227:Carbazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004247:DNA / Q000032:analysis; D004996:Ethidium / Q000494:pharmacology; D007364:Intercalating Agents / Q000138:chemical synthesis*; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D014783:Viscosity
D000970:Antineoplastic Agents; D002227:Carbazoles; D007364:Intercalating Agents; D004247:DNA; D004996:Ethidium