Alchemix: A novel alkylating anthraquinone with potent activity against anthracycline- and cisplatin-resistant ovarian cancer

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 IIalpha-DNA complexes over topo IIbeta-DNA complexes.