Mechanism of action of ferrocene derivatives on the catalytic activity of topoisomerase IIalpha and beta--distinct mode of action of two derivatives.
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 II 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 IIbeta activity. Thiomorpholide amido methyl ferrocene shows higher inhibition of catalytic activity (IC(50) = 50 microM) against topoisomerase IIbeta compared to azalactone ferrocene (IC(50) = 100 microM). 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 IIbeta.
Sai Krishna
A D
AD
Department of Biochemistry, University of Hyderabad, India.
Panda
Gayatri
G
Kondapi
Anand K
AK
D000251:Adenosine Triphosphatases / Q000737:chemistry; D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry*; D002384:Catalysis; D002417:Cattle; D004247:DNA / Q000737:chemistry; D004250:DNA Topoisomerases, Type II / Q000737:chemistry*; D004268:DNA-Binding Proteins / Q000737:chemistry*; D005296:Ferrous Compounds / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology*; D006358:Hot Temperature; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000737:chemistry*; D000075163:Metallocenes; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D008962:Models, Theoretical; D008968:Molecular Conformation; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology*; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D020033:Protein Isoforms; D021281:Quantitative Structure-Activity Relationship; D012984:Software; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013950:Thymus Gland / Q000378:metabolism
D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D005296:Ferrous Compounds; D007783:Lactones; D000075163:Metallocenes; D009025:Morpholines; D010080:Oxazoles; D020033:Protein Isoforms; C502556:azalactone ferrocene; C502555:thiomorpholide amido methyl ferrocene; D004247:DNA; D000251:Adenosine Triphosphatases; D004250:DNA Topoisomerases, Type II; C004998:ferrocene