Inhibition of Topoisomerase II Catalytic Activity by Two Ruthenium Compounds:  A Ligand-Dependent Mode of Action

Abstract

The ability of two structurally different ruthenium complexes to interfere with the catalytic activity of topoisomerase II was studied to elucidate their molecular mechanism of action and relative antineoplastic activity. The first complex, [RuCl2(C6H6)(dmso)], could completely inhibit DNA relaxation activity of topoisomerase II and form a drug-induced cleavage complex. This strongly suggests that the drug interferes with topoisomerase II activity by cleavage complex formation. The bi-directional binding of [RuCl2(C6H6)(dmso)] to DNA and topoisomerase II was verified by immunoprecipitation experiments which confirmed the presence of DNA and ruthenium in the cleavage complex. The second complex, Ruthenium Salicylaldoxime, could not inhibit topoisomerase II relaxation activity appreciably and also could not induce cleavage complex formation, though its DNA-binding characteristics and antiproliferation activity were almost comparable to those of [RuCl2(C6H6)(dmso)]. The results suggest that the difference in ligands and their orientation around a metal atom may be responsible for topoisomerase II poisoning by the first complex and not by the second. A probable mechanism is proposed for [RuCl2(C6H6)(dmso)], where the ruthenium atom interacts with DNA and ligands of the metal atom form cross-links with topoisomerase II. This may facilitate the formation of a drug-induced cleavage complex.

Cytotoxicity of half sandwich ruthenium(II) complexes with strong hydrogen bond acceptor ligands and their mechanism of action

“…The role of ruthenium or its mode of binding with the enzyme topoisomerase II or the DNA topoisomerase complex has not been elucidated. Initially, this mode of action was observed by Kondapi and coworkers with the piano stool ruthenium-benzene complex [29,30]. Recently, it has also been observed for the aromatic rings of ruthenium complexes with polypyridyl ligands [31,32].…”

Induced-fit recognition of DNA by organometallic complexes with dynamic stereogenic centers

“…In contrast to octahedral metallointercalators such as Tris-(phenanthroline)Ru(II) derivatives (20,32), [Ru(phenanthroline) 2 Cl 2 ] (33), and [Ru(bipyridine) 2 Cl 2 ] (34), which are essentially inert to racemization, have rigid frameworks, and recognize DNA mainly by shape-match (20), the {( 6 -arene)Ru(II)} complexes studied here have dynamic stereogenic centers and fluxional 6 -arene ligands. Binding of these Ru-(arene) complexes to DNA can be accompanied by configurational changes that allow recognition by an induced fit mechanism.…”

“…For example, Jaouen et al (2) have designed antiestrogenic cyclopentadienyl complexes that recognize the estrogen receptor and have potential for treatment of breast cancer, and other workers have also carried out pioneering studies on the recognition of nucleobases, amino acids, and peptides by organometallic centers (1,(3)(4)(5). However, as far as we are aware, there are few investigations of specific interactions of organometallic arene complexes with natural DNA (6).…”

“…We have discovered the anticancer potential of the ethylenediamine (en) complexes [( 6 -arene)RuCl(en)] ϩ , which exhibit in vitro and in vivo activity, for example in a cisplatin-resistant A2780 xenograft model of human ovarian cancer (10,11). The cytotoxicity appears to increase with increasing size of the 6 -arene. A potential target is DNA.…”

Synthesis of 4β-carbamoyl epipodophyllotoxins as potential antitumour agents

“…The topo-II-mediated relaxation assay performed is in accordance to the previously reported procedure. 17 …”