期刊
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
卷 438, 期 2, 页码 206-216出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2005.04.014
关键词
topoisomerase II alpha; topoisomerase II beta; ferrocene; quantitative structure-activity relationship; anti-cancer; topo II poisons
Topoisomerase II is found to be present in two isoforms alpha and beta and both the isoforms are regulated in cancerous tissue. Development of isoform-specific topoisomerase It poisons has been of great interest for cancer-specific drug targeting. In the present investigation using quantitative structure-activity analysis of ferrocene derivatives, we show that two derivatives of ferrocene, azalactone ferrocene and thiomorpholide amido methyl ferrocene, can preferentially inhibit topoisomerase II beta activity. Thiomorpholide amido methyl ferrocene shows higher inhibition of catalytic activity (IC50 = 50 mu M) against topoisomerase II beta compared to azalactone ferrocene (IC50 = 100 mu M). The analysis of protein DNA intermediates formed in the presence of these two compounds suggests that azalactone ferrocene readily induces formation of cleavable complex in a dose-dependent manner, in comparison with thiomorpholide amido methyl ferrocene. Both the compounds show significant inhibition of DNA-dependent ATPase activity of enzyme. These results suggest that azalactone ferrocene inhibits DNA passage activity of enzyme leading to the formation of cleavable complex, while thiomorpholide amido methyl ferrocene competes with ATP binding resulting in the inhibition of catalytic activity of enzyme. In summary, thiomorpholide amido methyl ferrocene and azalactone ferrocene show distinctly different mechanisms in inhibition of catalytic activity of topoisomerase II beta. (c) 2005 Elsevier Inc. All rights reserved.
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