Topoisomerase II poisoning by indazole and imidazole complexes of ruthenium.
Trans-imidazolium (bis imidazole) tetrachloro ruthenate (RuIm) and trans-indazolium (bis indazole) tetrachloro ruthenate (RuInd) are ruthenium coordination complexes, which were first synthesized and exploited for their anticancer activity. These molecules constitute two of the few most effective anticancer ruthenium compounds. The clinical use of these compounds however was hindered due to toxic side effects on the human body. Our present study on topoisomerase II poisoning by these compounds shows that they effectively poison the activity of topoisomerase II by forming a ternary cleavage complex of DNA, drug and topoisomerase II. The thymidine incorporation assays show that the inhibition of cancer cell proliferation correlates with topoisomerase II poisoning. The present study on topoisomerase II poisoning by these two compounds opens a new avenue for renewing further research on these compounds. This is because they could be effective lead candidates for the development of more potent and less toxic ruthenium containing topoisomerase II poisons. Specificity of action on this molecular target may reduce the toxic effects of these ruthenium-containing molecules and thus improve their therapeutic index.
Vashisht Gopal
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Department of Biochemistry, University of Hyderabad, Hyderabad 500 044, India.
Kondapi
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AK
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000633:toxicity; D007191:Indazoles / Q000494:pharmacology* / Q000633:toxicity; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009942:Organometallic Compounds / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017975:Ruthenium Compounds / Q000494:pharmacology* / Q000633:toxicity; D013936:Thymidine / Q000378:metabolism; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
C415339:(bisindazole)tetrachlororuthenate(III); D000970:Antineoplastic Agents; D007093:Imidazoles; D007191:Indazoles; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; D059005:Topoisomerase II Inhibitors; C048589:imidazolium-bis(imidazole)tetrachlororuthenate(III); D004247:DNA; D000251:Adenosine Triphosphatases; D004250:DNA Topoisomerases, Type II; D013936:Thymidine