Synthesis and evaluation of the antitumor activity of 2-substituted 1,4-dihydroxy-9,10-anthraquinones.

2-(1-Hydroxyiminoalkyl)-1,4-dimethoxy-9,10-anthraquinones were demethylated to produce 2-(1-hydroxyiminoalkyl)-1,4-dihydroxy-9,10-anthraquinones (1,4-dihydroxy-9,10-anthraquinone, DHAQ), oxime hydroxyl groups were in turn acylated to give the corresponding 2-(1-acyloxyiminoalkyl)-DHAQ derivatives. The anti-proliferative activity of 2-(1-hydroxyiminoalkyl)-DHAQ derivatives was found to be dependent on the size of an alkyl chain. Thus, DHAQ analogues with alkyl chains longer than heptyl had negligible anti-proliferative activity, whilst those compounds possessing shorter chains demonstrated moderate anti-proliferative activity (ED50, 2.73-19.21 microM). However, the antitumor activity as expressed by T/C values did not correlate with the anti-proliferative activity; 2-(1-hydroxyiminononyl)-DHAQ with an ED50 value of more than 20 microM exhibited potent antitumor activity (T/C, 166%). Only four of the 2-(1-hydroxyiminoalkyl)-DHAQ analogues showed good antitumor activity (T/C, > 150%); 2-(1-hydroxyiminobutyl)-DHAQ (T/C, 163%), 2-(1-hydroxyiminopentyl)-DHAQ (T/C, 180%) and 2-(1-hydroxyiminononyl)-DHAQ (T/C, 166%). Acylation of the hydroxyl group of these oximes enhanced the anti-proliferative activity and antitumor effects; 2-(1-propanoyloxyiminopropyl)-DHAQ (ED50, 4.41 microM; T/C, 221%) vs. 2-(1-hydroxyiminopropyl)-DHAQ (ED50, 14.64 microM; T/C, 100%) and 2-(1-propanoyloxyiminobutyl)-DHAQ (ED50, 2.65 microM; T/C, 202%) vs. 2-(1-hydroxyiminobutyl)-DHAQ (ED50, 16.43 microM; T/C, 163%).