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        Synthesis of DNA-directed pyrrolidinyl and piperidinyl confined alkylating chloroalkylaminoanthraquinones : potential for development of tumor-selective N-oxides

        Author
        Pors, Klaus
        Shnyder, Steven D.
        Teesdale-Spittle, Paul H.
        Hartley, John A.
        Zloh, Mire
        Searcey, Mark
        Patterson, Laurence H.
        Attention
        2299/11457
        Abstract
        A novel series of 1,4-disubstituted chloroethylaminoanthraquinones, containing alkylating chloroethylamino functionalities as part of a rigid piperidinyl or pyrrolidinyl ring-system, have been prepared. The target compounds were prepared by ipso-displacement of halides of various anthraquinone chromophores by either hydroxylated or chlorinated piperidinyl- or pyrrolidinyl-alkylamino side chains. The chloroethylaminoanthraquinones were shown to alkylate guanine residues of linearized pBR322 (1-20 microM), and two symmetrically 1,4-disubstituted anthraquinones (compounds 14 and 15) were shown to interstrand cross-link DNA in the low nM range. Several 1,4-disubstituted chloroethylaminoanthraquinones were potently cytotoxic (IC50 values: ≤40 nM) in human ovarian cancer A2780 cells. Two agents (compounds 18 and 19) exhibited mean GI50 values of 96 nM and 182 nM, respectively, in the NCI human tumor cell line panel. Derivatization of the potent DNA cross-linking agent 15 to an N-oxide resulted in loss of the DNA unwinding, DNA interstrand cross-linking and cytotoxic activity of the parent molecule
        Publication date
        2006
        Published in
        Journal of Medicinal Chemistry
        Published version
        https://doi.org/10.1021/jm0608154
        Other links
        http://hdl.handle.net/2299/11457
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