Naphthazarin derivatives: Synthesis, cytotoxic mechanism and evaluation of antitumor activity

The rate of the GSH conjugate formation, the inhibition of DNA topoisomerase-I and the cytotoxic activity against L1210 cells of the naphthoquinones showed the same order; 5,8-dimethoxy-1,4-naphthoquinone (DMNQ) > 6-(1-hydroxyethyl)-DMNQ>2-(1-hydroxyethyl)-DMNQ; the steric hindrance of the substituents, particularly 2-substutuent, in reacting with cellular nucleophiles must be the main cause for lowering the bioactivities. Acerylation of 2-(1-hydroxyethyl)-DMNQ producing 2-(acetyloxyethyl)-DMNQ potentiated the bioactivities; 2-(1-hydroxyethyl)-DMNQ did not react with GSH and the enzyme, and showed ED₅₀ of 0.680 μg/ ml, whereas the values of 2-(1-acetyloxyethyl)-DMNQ were the conjugate formation of 0.14 μM, IC₅₀ value of 81 μM for the enzyme inhibition and ED₅₀ of 0.146 μg/ml for the cytotoxcity. Furthermore, the acetylation 2-(1-hydroxyethyl)-DMNQ (T/C, 119%) enhaced the T/C values for the mice bearing S-180 tumor [T/C of 2-(1-acetyloxyethyl)-DMNQ, 276%]. It was assumed that the difference in bioactivities ensued by acetylation was based on the mechanism of the so-called bioreductive alkylation.