ABSTRACT
We have synthesized cis-[Ru(bpy)2(NO2-κN)Ln-](n-1) and cis-[Ru(bpy)2(NO2-κO)L n-](n-1) (bpy = 2,2'-bipyridine; k = indication of the coordinated center to Ruthenium; L = pyridine type ligand) by reacting cis-[Ru(bpy)2(H2O)Ln-](n-2) with sodium nitrite or conducting basic cis-[Ru(bpy)2NO(Ln-)](n-3) hydrolysis. Photolysis at the metal-ligand charge transfer band (MLCT) of the isomers yielded nitric oxide (NO) as determined by NO measurement. The NO photorelease rates obtained upon 447 nm laser irradiation of the ruthenium complexes showed that cis-[Ru(bpy)2(NO2-κO)Ln-](n-1) released NO three times faster than cis-[Ru(bpy)2(NO2-κN)Ln-](n-1). We investigated endothelium-dependent vasodilation induced by cis-[Ru(bpy)2(4-pic)(NO2-κN)]+ and cis-[Ru(bpy)2(4-pic)(NO2-κO)]+ (4-pic = 4-picoline) in isolated 3 mm aortic rings precontracted with L-phenylephrine. Maximum vasodilation was achieved under 447 nm laser irradiation of 0.5 µMol.L-1 ruthenium complexes for 100 s.
Subject(s)
Ruthenium , Vasodilator Agents , Isomerism , Ruthenium/pharmacology , Ruthenium/chemistry , Nitric Oxide , Ligands , Nitrogen DioxideABSTRACT
Cyclometallated palladium(ii) and platinum(ii) pyrenyl-derived thiosemicarbazone (H2PrR) complexes of the type [M4(µ-S-PrR-κ3-C,N,S)4] (M = PdII, PtII; R = ethyl, cyclohexyl) have been synthesised in good yields and fully characterised. X-ray crystallography showed that the tetranuclear complex [Pt4(µ-S-PrCh-κ3-C,N,S)4](CH3)2COCHCl3 contains an eight-membered ring of alternating M-S atoms. The ethyl derivatives [M4(µ-S-PrEt-κ3-C,N,S)4] exhibit potent antiproliferative activity towards A2780 human ovarian cancer cells, with IC50 values of 1.27 µM (for M = PdII) and 0.37 µM (for M = PtII), the latter being an order of magnitude more potent than the anticancer drug cisplatin (IC50 1.20 µM). These promising complexes had low toxicity towards non-cancerous human MRC5 cells, which points towards an early indication of differential toxicity between cancer and normal cells. Experiments that investigated the effects of these tetranuclear complexes on the cell cycle, integrity of the cell membrane, and induction of apoptosis, suggested that their mechanism of action of does not involve DNA targeting, unlike cisplatin, and therefore could be promising for combatting cisplatin resistance.
Subject(s)
Antineoplastic Agents/pharmacology , Coordination Complexes/pharmacology , Palladium/pharmacology , Platinum/pharmacology , Pyrenes/pharmacology , Thiosemicarbazones/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Humans , Models, Molecular , Molecular Structure , Palladium/chemistry , Platinum/chemistry , Pyrenes/chemistry , Thiosemicarbazones/chemistryABSTRACT
New palladium complexes with thiosemicarbazonate ligands derived from pyrene exhibit potent antiproliferative activity against A2780 and cisplatin-resistant A2780Cis human ovarian cancer cells, which is dependent on substituent groups of the thiosemicarbazone ligands. Cellular accumulation and distribution studies confirmed that palladium enters the cell nucleus. DNA and topoisomerase IB studies show that one complex is a potent TopIB inhibitor, with selectivity for cancer versus normal cells.
