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Tacrine derivatives as dual topoisomerase I and II catalytic inhibitors
J. Janočková, J. Plšíková, J. Koval', R. Jendželovský, J. Mikeš, J. Kašpárková, V. Brabec, S. Hamuľaková, P. Fedoročko, M. Kožurková,
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Apoptosis drug effects MeSH
- DNA Topoisomerases metabolism MeSH
- DNA metabolism MeSH
- HL-60 Cells MeSH
- Topoisomerase I Inhibitors chemistry pharmacology MeSH
- Topoisomerase II Inhibitors chemistry pharmacology MeSH
- Intercalating Agents chemistry pharmacology MeSH
- Leukemia drug therapy metabolism MeSH
- Humans MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents chemistry pharmacology MeSH
- Tacrine chemistry pharmacology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
This study examines the binding properties of a series of newly synthetized tacrine derivatives 1-4 and their anticancer effects. Spectroscopic techniques (UV-Vis, fluorescence spectroscopy, thermal denaturation, and linear spectropolarimetry) and viscometry were used to study DNA binding properties and to determine the types of DNA interaction with the studied derivatives. The binding constants for the complexes with DNA were obtained using UV-Vis spectroscopic titrations (K = 1.6 × 10(4)-4.0 × 10(5) M(-1)) and electrophoretic methods were used to determine the effect of the derivatives on topoisomerase I and II activity. Monotacrine derivative 1 showed evidence of topoisomerase Irelaxation activity at a concentration of 30 × 10(-6) M, while bistacrine derivatives 2-4 produced a complete inhibition of topoisomerase Iat a concentration of 5 × 10(-6) M. The biological activities of the derivatives were studied using MTT-assay and flow cytometric methods (detection of mitochondrial membrane potential and measurement of cell viability) following incubation of 24 and 48 h with human leukemic cancer cell line HL60. The ability of the derivatives to impair cell proliferation was also tested through the analysis of cell cycle distribution.
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- $a Janočková, Jana $u Department of Biochemistry, P. J. Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovak Republic.
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- $a This study examines the binding properties of a series of newly synthetized tacrine derivatives 1-4 and their anticancer effects. Spectroscopic techniques (UV-Vis, fluorescence spectroscopy, thermal denaturation, and linear spectropolarimetry) and viscometry were used to study DNA binding properties and to determine the types of DNA interaction with the studied derivatives. The binding constants for the complexes with DNA were obtained using UV-Vis spectroscopic titrations (K = 1.6 × 10(4)-4.0 × 10(5) M(-1)) and electrophoretic methods were used to determine the effect of the derivatives on topoisomerase I and II activity. Monotacrine derivative 1 showed evidence of topoisomerase Irelaxation activity at a concentration of 30 × 10(-6) M, while bistacrine derivatives 2-4 produced a complete inhibition of topoisomerase Iat a concentration of 5 × 10(-6) M. The biological activities of the derivatives were studied using MTT-assay and flow cytometric methods (detection of mitochondrial membrane potential and measurement of cell viability) following incubation of 24 and 48 h with human leukemic cancer cell line HL60. The ability of the derivatives to impair cell proliferation was also tested through the analysis of cell cycle distribution.
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- $a Plšíková, Jana $u Department of Biochemistry, P. J. Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovak Republic.
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