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

Some 2- or 6-acyl-5,8-dimethoxy-1,4-naphthoquinone (DMNQ) derivatives were synthesized and evaluated for inhibition of DNA topoisomerase I and cytotoxicity against L1210 cells. Compared with 2-acyl-DMNQ derivatives, 6-acyl-DMNQ compounds, bearing a higher electrophilic quinone moiety, showed a higher potency in the inhibition of DNA topoisomerase I and the cytotoxicity, implying the possible participation of electrophilic arylation in their bioactivities. Time and temperature dependence of the enzyme inhibition suggests 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)) showed higher potency in their bioactivities than other derivatives. Furthermore, for the effective inhibition of DNA topoisomerase I, the size of acyl moiety of 6-acylated derivatives seems to be limited to < 12 carbon atoms.