Synthesis and in vitro antitumor activity of substituted anthracene-1,4-diones

Based on a rational approach, 6-substituted 1,4-anthracenediones were synthesized and found to exhibit potent cytotoxic activity against murine and human leukemic cells. The synthetic sequence includes a double Friedel–Crafts reaction, reductive quinone formation, and selective bromination of the alkyl side chain. A key intermediate, 6-bromomethyl-1,4-anthracenedione (), was synthesized and converted to various active antitumor agents, including a water-soluble phosphate ester pro-drug. The interconversion reactions include displacement of the bromide with various nucleophiles and basic hydrolysis to the alcohol and subsequent oxidation to provide the aldehyde. Based on their ability to decrease L1210 and HL-60 tumor cell viability, 1,4-dihydroxyanthraquinones are inactive but 1,4-anthracenediones have interesting antitumor activity, which may be abolished by modification of the A-ring and improved by substitution of the C-ring. The cytostatic and cytotoxic activity of the representative compound was verified at the National Cancer Institute in studies on the 60-human tumor cell line panel in the in vitro antitumor screening. A wide spectrum of tumor cells are sensitive to inhibition, and concentrations required to inhibit tumor cell growth by 50% (GI50) at 48 h are <10 nM in HL-60 and MOLT-4 and 37.1 nM in SR leukemia. Preliminary studies suggest that the molecular targets and mechanisms of action of may be different from those of daunomycin.