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Department of Pharmaceutical and Biological Chemistry, The School of Pharmacy, University of London, London WC1N 1AX, United Kingdom [K. P., L. H. P.]; Department of Pharmacy, De Montfort University, Leicester LE1 9BH, United Kingdom [Z. P., P. T. S.]; Cancer Research UK Department of Medical Oncology, University of Glasgow, Glasgow G61 1BD, United Kingdom [J. A. P.]; and School of Cell and Molecular Biosciences, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, United Kingdom [E. W., C. A. A.]

² To whom requests for reprints should be addressed, at Department of Pharmaceutical and Biological Chemistry, The School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, United Kingdom

Chloroethylaminoanthraquinones are described with intercalating and alkylating capacity that potentially covalently cross-link topoisomerase II (topo II) to DNA. These compounds have potent cytotoxic activity (IC₅₀ = 0.9–7.6 nM) against the A2780 human ovarian carcinoma cell line. Hydroxyethylaminoanthraquinones also reported in this paper have similar IC₅₀ values (0.7–1.7 nM) in the same cell line. Alchemix (ZP281M, 1-{2-[N,N-bis(2-chloroethyl)amino]ethylamino}-4-{2-[N,N-(dimethyl)amino]ethylamino}-5,8-dihydroxy-9,10-anthracenedione), an alkylating anthraquinone, retains excellent antitumor activity in Adriamycin-resistant (2780AD) and cisplatin-resistant (2780/cp70) cell lines in vitro and in vivo. This indicates that Alchemix can evade both P-glycoprotein efflux pump and DNA mismatch repair-mediated resistance. In treated cells, Alchemix was shown to preferentially induce drug-stabilized covalent bound topo II-DNA complexes over topo IIß-DNA complexes.