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

Pors, K., Shnyder, S.D., Teesdale-Spittle, P.H., Hartley, J.A., Zloh, M., Searcey, M. and Patterson, L.H. (2006) Synthesis of DNA-directed pyrrolidinyl and piperidinyl confined alkylating chloroalkylaminoanthraquinones: potential for development of tumor-selective N-oxides. Journal of Medicinal Chemistry, 49 (24). pp. 7013-7023. 10.1021/jm0608154.

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DOI: 10.1021/jm0608154

Abstract

Synthesis of DNA-Directed Pyrrolidinyl and Piperidinyl Confined Alkylating Chloroalkylaminoanthraquinones: Potential for Development of Tumor-Selective N-Oxides Klaus Pors, Steven D. Shnyder, Paul H. Teesdale-Spittle, John A. Hartley, Mire Zloh, Mark Searcey, and Laurence H. Patterson* Institute of Cancer Therapeutics, University of Bradford, West Yorkshire, BD7 1DP, United Kingdom, School of Biological Sciences, Victoria University of Wellington, Post Office Box 600, Wellington, New Zealand, and Cancer Research UK Drug-DNA Interactions Research Group, Department of Oncology, University College London, School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, United Kingdom Received July 11, 2006 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 M), 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.

Item Type:Article
Additional Information:Full text available in print and electronically at the School of Pharmacy Library.
Departments, units and centres:Department of Pharmaceutical and Biological Chemistry > Department of Pharmaceutical and Biological Chemistry
ID Code:746
Journal or Publication Title:Journal of Medicinal Chemistry
Deposited By:Library Staff
Deposited On:17 Apr 2007
Last Modified:24 Oct 2007 10:16

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