Interactions of antitumor triazoloacridinones with DNA

• Authors: Marcin Koba , Jerzy Konopa
• Languages of publication: EN

Abstracts

EN

Triazoloacridinones (TA) are a new group of potent antitumor compounds, from which the most active derivative, C-1305, has been selected for extended preclinical trials. This study investigated the mechanism of TA binding to DNA. Initially, for selected six TA derivatives differing in chemical structures as well as cytotoxicity and antitumor activity, the capability of noncovalent DNA binding was analyzed. We showed that all triazoloacridinones studied stabilized the DNA duplex at a low-concentration buffer but not at a salt concentration corresponding to that in cells. DNA viscometric studies suggested that intercalation to DNA did not play a major role in the mechanism of the cytotoxic action of TA. Studies involving cultured cells revealed that triazoloacridinone C-1305 after previous metabolic activation induced the formation of interstrand crosslinks in DNA of some tumor and fibroblast cells in a dose dependent manner. However, the detection of crosslink formation was possible only when the activity of topoisomerase II in cells was lowered. Furthermore, it was impossible to validate the relevance of the ability to crosslink DNA to biological activity of TA derivatives.

Keywords

EN

biological activity; triazoloacridinones; DNA intercalation; DNA interstrand crosslinks; structure-activity relationship; metabolic activation

• Publisher: Polish Biochemical Society
• Journal: Acta Biochimica Polonica
• Year: 2007
• Volume: 54
• Issue: 2
• Pages: 297-306

Dates

published

2007

received

2007-02-12

revised

2007-03-20

accepted

2007-03-21

(unknown)

2007-04-19

Contributors

author

Marcin Koba

• Department of Pharmaceutical Technology and Biochemistry University of Technology, Gdańsk, Gdańsk, Poland

author

Jerzy Konopa

• Department of Pharmaceutical Technology and Biochemistry University of Technology, Gdańsk, Gdańsk, Poland

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