Topoisomerase II antagonism and anticancer activity of coordinated derivatives of [RuCl(2)(C(6)H(6))(dmso)].
Topoisomerase II poisoning and anticancer activity by the organometallic compound [RuCl(2)(C(6)H(6))(dmso)] was shown by us in an earlier study [Biochemistry 38 (1999) 4382]. Since high concentrations of this complex were required to achieve either effects, we have synthesized four derivatives of this complex in which the dimethyl sulphoxide group on the ruthenium atom was replaced with pyridine, 3-aminopyridine, p-aminobenzoic acid, and aminoguanidine. Three of these molecules showed enhanced potency of topoisomerase II poisoning and consequently also showed higher anticancer activity in breast and colon carcinoma cells in vitro. Detailed analysis of the molecular action of these compounds on topoisomerase II activity was carried out using the classical relaxation and cleavage activity of the enzyme, which revealed that the compounds poison topoisomerase II by freezing the enzyme and enzyme-cleaved DNA in a ternary "cleavage complex". The cleavage complex is implicated in the anti-neoplastic activity of these compounds. DNA interaction studies showed that these compounds interact with DNA in much the same way as [RuCl(2)(C(6)H(6))(dmso)], by external binding of the DNA helix. This is unlike most other topoisomerase II poisons, which predominantly interact with DNA through intercalation with the double helix.
Vashisht Gopal
Y N
YN
Department of Biochemistry, School of Life Sciences, University of Hyderabad, 500046, India.
Konuru
Neelima
N
Kondapi
Anand K
AK
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000737:chemistry; D004273:DNA, Neoplasm / Q000737:chemistry / Q000187:drug effects; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology; D009942:Organometallic Compounds / Q000494:pharmacology*; D051381:Rats; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D007364:Intercalating Agents; D009942:Organometallic Compounds; C118522:Ruthenium Ben; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II; D004121:Dimethyl Sulfoxide