2-(1-Oxyalkyl)-1,4-dioxy-9,10-anthraquinones: Synthesis and evaluation of antitumor activity

Fourty eight derivatives of 2-(1-oxyalkyl)-1,4-dioxy-9,10-anthraquinone were synthesized, and their antitumor activity was evaluated. On the whole, 2-(1-hydroxyalkyl)-1,4-dihydroxy-9,10-anthraquinones (DHAQ=1,4-dihydroxy-9,10-anthraquinone) showed stronger cytotoxic activity againnst L1210 cells than 2-(1-hydroxyalkyl)-1,4-dimethoxy.-9,10-anthraquinones(DMAQ=1,4-dimethoxy-9,10-anthraquinone), implying that free hydroxy groups at C-1 and C-4 of the anthraquinone structure are necessary for the cytotoxic activity. The bioactivity of 2-(1-hydroxyalkyl)-DHAQ derivatives differed according to the size of alkyl group at C-1, while the elongation of alkyl group over 7 carbon atoms failed to enhance, the bioactivity, the derivatives possessing alkyl moiety of 1–6 carbon atoms showed an increase in the cytotoxicity and the antitumor activity in Sarcoma-180; 2-hydroxymethyl-DHAQ (ED₅₀, 15 μg/ml; T/C, 125%), 2-(1-hydroxyethyl)-DHAQ(1.9 μg/ml; 139.2%), 2-(1-hydroxypropyl)-DHAQ (7.2 μg/ml; 135.1%), 2-(1-hydroxybutyl)-DHAQ (10.2 μg/ml; 125.3%), 2-(1-hydroxypentyl)-DHAQ (23.7 μg/ml; 110.1%) and 2-(1-hydroxyhexyl)-DHAQ (58 μg/ml; 108%). Next, 2-(1-Hydroxyalkyl)-DHAQ derivatives were acetylated to produce 2-(1-acetoxyalkyl)-DHAQ analogues. Although the acetylation somewhat enhanced the cytotoxicity, but not the antitumor action. In addition, the presence of phenyl group at C-1' enhanced the cytotoxicity and the T/C value, compared to alkyl groups of same size; 2-(1-hydroxy-1-phenyl)-DHAQ (ED₅₀, 5.6 μg/ml; T/C., 137%).