Synthesis of 11H-pyridocarbazoles and derivatives. Comparison of their DNA binding and antitumor activity with those of 6H- and 7H-pyridocarbazoles.
The 8-methoxy- and 8-hydroxy-11H-pyrido[2,3-a]-, -[3,4-a]-, -[4,3-a]-, and [3,2-a]carbazoles were synthesized as potential DNA intercalating antitumor drugs. The structure of these compounds was confirmed by 1H NMR study including NOE experiments. The DNA binding properties of substituted and unsubstituted (8-H) heterocycles were determined by using their hydrochlorides or methiodides. These derivatives are able to bind to DNA with an affinity varying from 2.0 X 10(4) to 1.0 X 10(6) M-1, but most of them are unable to intercalate in contrast with the behavior of 6H- and 7H-pyridocarbazole analogues. The cytotoxicity of 11H-pyridocarbazoles, measured on L1210 cells in vitro, is much lower than those of 6H- and 7H-pyridocarbazole analogues.
D000470:Alkaloids / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002417:Cattle; D055598:Chemical Phenomena; D002621:Chemistry; D004247:DNA / Q000378:metabolism*; D004611:Ellipticines / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use*; D007364:Intercalating Agents; D007939:Leukemia L1210 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy
D000470:Alkaloids; D000970:Antineoplastic Agents; D004611:Ellipticines; D007364:Intercalating Agents; D004247:DNA