2-SUBSTITUTED NAPHTHAZARINS - SYNTHESIS AND ANTITUMOR-ACTIVITY

A series of 2-substituted naphthazarin derivatives, 5,8-dihydroxy-1,4- naphthoquinone (DHNQ) derivatives and 5,8-dimethoxy-1,4-naphthoquinone (DMNQ) derivatives, were synthesized, and their cytotoxic activity ag ainst some cancer cell lines and antitumor action against S-180 tumor were evaluated. In general; 2-(1-hydroxyalkyl)-DHNQ derivatives showed a higher cytotoxicity than 2-(l-hydroxyalkyl)-DMNQ derivatives, imply ing a predominent role of redox cycling rather than electrophilicity i n cytotoxicity. 2-(1-Alkoxy-4-methylpentyl) or 2-(1-acyloxy-4-methylpe ntyl) derivatives were produced by alkylation or acylation at the C-1' position of 2-(1-hydroxy-4-methylpentyl)-DHNQ or DMNQ derivatives. Al though the cytotoxicity differed according to the size of the alkyl or acyl chain, alkylation or acylation at the C-1' position did not impr ove the cytotoxicity remarkably, and DHNQ derivatives were still more cytotoxic than DMNQ derivatives. Separately, in vivo testing showed th at 2-(1-acyloxyalkyl)-DHNQ derivatives or 2-(1-alkoxyalkyl)-DHNQ deriv atives expressed a higher antitumor action than 2-(1-hydroxyalkyl)-DMN Q or -DHNQ derivatives in contrast to the cytotoxicity observations. T he total size of two side chains at C-1' seemed to govern the antitumo r activity, with 9 to 11 carbon atoms being optimal. Thus, it is sugge sted that the physical properties as well as the chemical reactivity a re to be considered in relation to the antitumor action of 2-substitut ed naphthazarin compounds.