Biological properties of 5,11-dimethyl-6H-pyrido[3,2-b]carbazoles: a new class of potent antitumour drugs

Thirteen 5,11-dimethyl-6H-pyrido[3,2-b]carbazoles structurally related to t he antitumour drug ellipticine, were tested for their cytotoxicity against the L1210 murine leukaemia cell line and their antitumour activity against both leukaemias and solid tumours. Most of them showed an interesting antit umour activity against L1210 leukaemia, 4-hydroxy-9-chloro-2,3, 5,11-tetram ethyl-6H-pyrido[3,2-b]carbazole displaying a high antitumour activity again st L1210 and P388 leukaennias, B16 melanoma and M5076 sarcoma. Despite prom ising cytotoxic activity, 4-ethoxy-5,11-dimethyl-6H-pyrido-[3,2-b]carbazole had no antitumour activity. The ability of four drugs to induce strand bre aks in DNA was studied using the single cell gel electrophoresis assay (com et assay). Most of the molecules induced DNA breaks that were totally or pa rtially repaired after 1 h, The effects of these compounds on the L1210 cel l cycle were tested as well as their abilities to induce apoptosis in these cells, Three of them induced a G(2)/M blockade, without any obvious eviden ce of apoptosis. The other compound, 4-ethoxy-5,11-dimethyl-6H-pyrido [3,2] carbazole, did not lead to phase-specific blockade, but was a strong induct or of apoptosis in L1210 cells.