2-Methylanthraquinone derivatives as potential bioreductive alkylating agents

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Abstract
Hypoxic cells of solid tumors are an obstacle to effective cancer therapy. Since hypoxic cells remote from the tumor blood supply may have a greater capacity for reductive reactions than well-oxygenated cells, a series of anthraquinone prodrugs were prepared which may be capable of generating a reactive quinonemethide species following enzymatic reduction to the hydroquinone and loss of the substituent on the methylene group in the 2 position. The synthesized 2-methyl-substituted anthraquinone derivatives have 1st half-wave reduction potentials of -0.52 to -0.56 V at pH 7.0, which are the lowest oxidation-reduction potentials of quinone bioreductive alkylating agents synthesized to date. Tests of the cytotoxicity of these agents to oxygenated and chronically hypoxic [mouse mammary] EMT6 tumor cells in culture demonstrated that 2-(hydroxymethyl)anthraquinone, 2-[(N-methylcarbamyl)methyl]anthraquinone, 2-[[(p-toluenesulfonyl)oxy]methyl]anthraquinone and 2-(methoxymethyl)anthraquinone were significantly more toxic to hypoxic cells than to their normally aerated counterparts. The findings demonstrate differences between various leaving groups in the 2 position for the expression of differential cytotoxicity.