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Antitumor Polycyclic Acridines. Part 16. Triplex DNA as a Target for DNA-Binding Polycyclic Acridine Derivatives

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Abstract:

Triple-stranded DNA structures have been implicated in a number of major biological processes, including the transcription and translation of a number of genes, as well as in the interaction of DNA with a number of proteins. Furthermore, antigene therapies under development are based on the recognition and binding of a single oligonucleotide strand to a double-stranded sequence, thus forming a triple helix. Triplex DNA formation is a relatively weak and temporary phenomenon; therefore, molecules that selectively bind to and stabilize triple helices may show a variety of novel biological effects. The biophysical and biological characterization of a series of antitumor polycyclic acridines that bind to triplex DNA is reported. These compounds, whose synthesis has been previously reported, have been tested for their interaction with both purine and pyrimidine type triple helices and compared with the relevant double-stranded DNA. As a pyrimidine triplex model we have used the T*AT sequence, which we have compared with the AT duplex, whereas the purine triplex oligonucleotide d[G3A4G3]*d[G3A4G3]·d[C3T4C3] has been compared with the duplex d[G3A4G3]·d[C3T4C3]. The compounds demonstrate various degrees of preferential binding to triplex DNA over normal duplex DNA, as measured by UV, fluorescence, circular dichroism, and thermal denaturation. Tri-substituted acridine derivatives demonstrated the highest affinity and ability to stabilize triplex DNA structures. Furthermore, structure/affinity analysis gives insights into the structural features that optimize affinity and selectivity for triplex DNA, and may play a role in their profile of antitumor activity.

Keywords: Circular dichroism; DNA binding; Fluorescence; Polycyclic acridine derivatives; Spectrophotometric analysis; Thermal denaturation; Triplex DNA; UV

Document Type: Research Article

DOI: http://dx.doi.org/10.3727/096504005775082002

Affiliations: 1: Chemistry Department, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK 2: Cancer Research UK Experimental Cancer Chemotherapy Research Group, Centre for Bio-molecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, NG7 2RD, UK

Publication date: February 1, 2005

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  • Formerly: Oncology Research Incorporating Anti-Cancer Drug Design
    Oncology Research Featuring Preclinical and Clincal Cancer Therapeutics publishes research of the highest quality that contributes to an understanding of cancer in areas of molecular biology, cell biology, biochemistry, biophysics, genetics, biology, endocrinology, and immunology, as well as studies on the mechanism of action of carcinogens and therapeutic agents, reports dealing with cancer prevention and epidemiology, and clinical trials delineating effective new therapeutic regimens.
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