Naphthazarin derivatives (IV): synthesis, inhibition of DNA topoisomerase I and cytotoxicity of 2-or 6-acyl-5,8-dimethoxy-1,4-naphahoquinones

Some 2- or 6-acyl-5,8-dimethoxy-1, 1-naphthoquinone (DMNQ) derivatives were synthesized and evaluated for inhibition of DNA topoisomerase I and cytoto xicity against L1210 cells. Compared with 2-acyl-DMNQ derivatives, 6-acyl-D MNQ compounds, bearing a higher electrophilic quinone moiety, showed a high er potency in the inhibition of DNA topoisomerase I and the cytotoxicity, i mplying the possible participation of electrophilic arylation in their bioa ctivities. Time and temperature dependence of the enzyme inhibition suggest s that the arylation occurs irreversibly. Among the 6-acyl-DMNQ derivatives , the ones possessing an acyl group of an intermediate size (C-5-C-9) showe d higher potency in their bioactivities than other derivatives. Furthermore , for the effective inhibition of DNA topoisomerase I, the size of acyl moi ety of 6-acylated derivatives seems to be limited to < 12 carbon atoms. (C) 2000 Editions scientifiques er medicales Elsevier SAS.