Palanisamy Uma Maheswari

The Square-Planar Cytotoxic [CuII(pyrimol)Cl] Complex Acts as an Efficient DNA Cleaver without Reductant

Chemical nucleases based on the transition-metal ions cleave DNA hydrolytically and/or oxidatively, with or without added reductant. We report here the novel DNA cleavage properties of the highly water-soluble, square-planar [Cu(Hpyrimol)Cl] complex, together with the results of cytotoxicities toward selected cancer cell lines. The copper complex cleaves PhiX174 supercoiled DNA efficiently without any reductant and shows high cytotoxicities toward L1210 murine leukemia and A2780 human ovarian carcinoma cancer cell lines that are sensitive and resistant to cisplatin. The IC50 values obtained for the copper complex in the sensitive cell lines are in the range of cisplatin, and for the cisplatin-resistant leukemia cell line, this value is even better.

Structure, Cytotoxicity, and DNA-Cleavage Properties of the Complex [CuII(pbt)Br2]

The reactions of the ligand 2-(2-pyridyl)benzthiazole (pbt) with CuBr 2 and ZnCl 2 in acetonitrile produce the complexes [Cu(pbt)Br 2] ( 1) and [Zn(pbt)Cl 2] ( 3), respectively. When complex 1 is dissolved in DMF, complex 2 is obtained as light-green crystals. The reaction of pbt with CuBr 2 in DMF also yields the complex [Cu(pbt)Br 2(dmf)] ( 2) (dmf = dimethylformamide). Complexes 1- 3 were characterized by X-ray crystallography. Complexes 1 and 3 have distorted tetrahedral coordination environments, and complex 2 is constituted of two slightly different copper centers, both exhibiting distorted trigonal bipyramidal geometries. Complexes 1 and 2 cleave phiX174 phage DNA, both in the presence and the absence of reductant. The free ligand pbt does not show any DNA-cleaving abilities. The poor solubility of complex 3 makes it not applicable for biological tests. The occurrence of DNA breaks in the presence of various radical scavengers suggests that no diffusible radicals are involved in the DNA cleavage by complex 1, as none of the scavengers inhibit the cleavage reaction. The DNA-cleavage products are not religated with the enzyme T4 DNA ligase, which is an additional proof that the cleavage is nonhydrolytic. Most probably the cleaving reaction involves reactive oxygen species, which could not be trapped, leading to an oxidative mechanism. An easy oxidation of Cu (II)(pbt)Br 2 to Cu (III) in DMF and the reduction of the same to Cu (I), under similar electrochemical conditions may lead to the in situ activation of molecular oxygen, resulting in the formation of metal solvated nondiffusible radicals able to prompt the oxidative cleavage of DNA. Complex 1 and the pure ligand exhibit remarkable cytotoxic effects against the cancer cell lines L1210 and A2780 and also against the corresponding cisplatin-resistant mutants of these cell lines.

Phenanthroline derivatives with improved selectivity as DNA-targeting anticancer or antimicrobial drugs.

Phenanthroline derivatives are of interest due to their potential activity against cancer, and viral, bacterial, and fungal infections. In a search for highly specific antitumor and antibacterial compounds, we report the activities of 1,10‐phenanthroline‐5,6‐dione (phendione or L1), dipyrido[3,2‐a:2′,3′‐c]phenazine (dppz or L2), and their corresponding platinum complexes ([PtL1Cl2] and [PtL2Cl2]), and provide the solid‐state 3D structure for [PtL1Cl2]. It is generally known that a toxic metal ion coordinated to an active organic moiety leads to a synergistic effect; however, we report herein that the platinum complexes [PtL1Cl2] and [PtL2Cl2] have weaker activities relative to those of the free ligands, especially against bacteria. Testing these agents against a variety of human cancer cell lines revealed that L1 and [PtL1Cl2] were at least as active as cisplatin against several of the cell lines (including a cisplatin‐resistant cell line). The absence of antibacterial activity of [PtL1Cl2] removes the detrimental effect of phenanthrolines toward intestinal flora, suggesting a highly promising new strategy for the development of anticancer drugs with reduced side effects.

Ruthenium(III) Chloride Complex with a Tridentate Bis(arylimino)pyridine Ligand : Synthesis, Spectra, X-ray Structure, 9-Ethylguanine Binding Pattern, and In Vitro Cytotoxicity

The synthetic, spectroscopic, structural, and biological studies of a bis(arylimino)pyridine Ru(III) chloride compound containing the ligand, 2,6-bis(2,4,6-trimethylphenyliminomethyl)pyridine are reported. The bis(arylimino)pyridine ligand, with three donor nitrogen atoms, was synthesized by condensation of 2,6-pyridinedicarboxaldehyde with 2,4,6-trimethylaniline. The Ru(III) complex, with formula [RuCl 3(L1)](H 2O) (RuL1), where L1 = 2,6-bis(2,4,6-trimethylphenyliminomethyl)pyridine, was structurally determined on the basis of analytical and spectroscopic (IR, UV-vis, ESI-MS) studies. A straightforward strategy to fully characterize the paramagnetic compound using advanced (1)H NMR is reported. This new complex is a prototype for a series of new anticancer Ru(III) and Ru(II) compounds with improved cytostatic properties; likely to be modified in a desirable manner due to the relatively facile ligand modification of the bis(imino)pyridines and their molecular architecture. The present Ru(III) complex is the first example of this family of Ru(III)/Ru(II) anticancer compounds with the aimed physicochemical characteristics. Although the ligand itself is moderately active in selected cell lines (EVSA-T and MCF-7), the activity of the [Ru(L1)Cl 3] complex has increased significantly for a broad range of cancer cell lines tested in vitro (IC 50 values = 11 approximately 17 microM). Reaction of the RuL1 species with the DNA model base 9-ethylguanine (9EtGua) was found to produce in a redox reaction the species trans-[Ru(II)(L1)(9EtGua) 2(H 2O)](ClO 4) 2 (abbreviated as RuL1-9EtGua), which was studied in solution and also in the solid state, by X-ray crystallography. The structure comprises the as yet unknown trans-bis(purine)Ru(II) unit.

A new family of Ru(II) complexes with a tridentate pyridine Schiff-base ligand and bidentate co-ligands: synthesis, characterization, structure and in vitro cytotoxicity studies

Starting from the Ru(III) complex, [RuCl3(L1)](H2O) (L1: 2,6-bis(2,4,6-trimethylphenyliminomethyl)pyridine), the chemical reactivity and cytotoxic activity of a new family of Ru(II) complexes with a number of bidentate co-ligands have been studied. The synthesis of the Ru(II)-bis(arylimino)pyridine complexes with the co-ligands 1,10-phenanthroline (phen), 2,2′dipyridyl-(bpy), 2-(phenylazo)pyridine (azpy), 2-(phenylazo)-3-methylpyridine (3mazpy), 2-(tolylazo)pyridine (tazpy), and 2-picolinate (pic) is reported. These new six complexes, with L1 and different bidentate N donor co-ligands, have been designed to allow the binding of a monodentate chloride ligand, which would be easily hydrolysed in vitro. Elemental analysis and several spectroscopic techniques (IR, UV-Vis, 1D and 2D 1H NMR and ESI-MS) have been used for the characterization of the new Ru(II) compounds. In addition, the crystal structure of the chlorido(2-picolinato)(2,6-bis(2,4,6-trimethylphenyliminomethyl)pyridine)ruthenium(II) was solved and shows a slightly distorted octahedral geometry for the Ru(II) centre with the tridentate L1 ligand coordinated in a planar mer fashion, with the bidentate ligand in a perpendicular orientation and a monodentate chloride, trans to the coordinating oxygen of the picolinate ion. The in vitro cytotoxic properties of these new Ru(II) complexes in comparison with the parent, starting Ru(III)-compound (IC50 values = 11–17 μM) appear to be encouraging for a broad range of cancer cell-lines tested (IC50 values = 0.4–10 μM). Some of them show better cytotoxic effects than cisplatin on a straight comparison with the same cancer cell lines. The cytotoxicity data are discussed in the light of structure–activity relationships and these ruthenium(II) compounds could well be promising next generation candidates worth further investigation.