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 μM). 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 μM 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‐hydroxyimino‐pentyl)‐ 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 μM; T/C, 221%) vs. 2‐(1‐hydroxyiminopropyl)‐DHAQ (ED50, 14.64 μmM; T/C, 100%) and 2‐(1‐propanoyloxyiminobutyl)‐DHAQ (ED50, 2.65 μM; T/C, 202%) vs. 2‐(1‐hydroxyiminobutyl)‐DHAQ (ED50, 16.43 μM; T/C, 163%).