Naphthazarin derivatives (VIII): Synthesis, inhibitory effect on DNA topoisomerase-I, and antiproliferative activity of 6-(1-acyloxyalkyl)-5,8-dimethoxy-1,4-naphthoquinones.

6-(1-Acyloxyalkyl)-5,8-dimethoxy-1,4-naphthoquinone (DMNQ; 5,8-dimethoxy-1,4-naphthoquinone) derivatives were synthesized and examined for their inhibitory effect on DNA topoisomerase-I (Topo I) and their antiproliferative activity against L1210 cells. The Topo-I inhibitory effect of 6-(1-hydroxyalkyl)-DMNQ derivatives was found to be dependent on the size of the alkyl chains, suggesting that lipophilicity might be one important factor influencing the inhibitory effect. It was found that acylation of 6-(1-hydroxyalkyl)-DMNQ derivatives possessing alkyl chains of C2-C5 enhanced both bioactivities, suggesting that an increase of electrophilicity in the quinoid moiety makes the electrophilic arylation of bionucleophiles more favorable. It is noteworthy that 6-(1-heptanoyloxyethyl)-DMNQ exhibited both the most potent Topo I inhibitory activity (IC50, 11.5 microM) and the greatest antiproliferative activity (ED50, 0.05 microM) upon L1210 cells.