Naphthazarin derivatives (VI): Synthesis, inhibitory effect on DNA topoisomerase-I and antiproliferative activity of 2- or 6-(1-oxyiminoalkyl)- 5,8-dimethoxy-1,4-naphthoquinones

Abstract

2- or 6-(1-Hydroxyiminoalkyl)-5,8-dimethoxy-1,4-naphthoquinone (DMNQ) and 6-(1-propyloxyimino-alkyl)-DMNQ derivatives were synthesized, and their inhibitory effects on DNA topoisomerase-I (TOPO-I) and antiproliferative activities against L1210 cells were examined. In a comparison, it was found that 6-(1-hydroxyiminoalkyl)-DMNQ derivatives exhibited higher potencies in both bioactivities than 2-(1-hydroxyiminoalkyl)-DMNQ analogues, suggesting that the difference in bioactivities between two positional isomers might be due to the steric hindrance of the side chain. It is noteworthy that the optimal size of alkyl group for both bioactivities of 6-(1- hydroxyiminoalkyl)-DMNQ derivatives was pentyl to octyl (IC50, 22-29 μM) for the inhibition of TOPO-I and propyl to nonyl (ED50, 0.12-0.19 μM) for the antiproliferative activity. In addition, a similar potency of bioactivities was expressed by 6-(1-propyloxyiminoalkyl)-DMNQ derivatives, propylation products of the oximes.