Zhen-Hua Liang

Synthesis of ruthenium(II) complexes and characterization of their cytotoxicity in vitro, apoptosis, DNA-binding and antioxidant activity

A new ligand DBHIP and its two ruthenium (II) complexes [Ru(bpy)(2)(DBHIP)](ClO(4))(2) (1) and [Ru(phen)(2)(DBHIP)](ClO(4))(2) (2) have been synthesized and characterized. The binding behaviors of the two complexes to calf thymus DNA were investigated by absorption spectra, viscosity measurements, thermal denaturation and photoactivated cleavage. The DNA-binding constants for complexes 1 and 2 have been determined to be 8.87+/-0.27 x 10(4)M(-1) (s=1.83) and 1.32+/-0.31 x 10(5)M(-1) (s=1.84). The results suggest that these complexes interact with DNA through intercalative mode. The cytotoxicity of DBHIP, complexes 1 and 2 has been evaluated by MTT assay. The apoptosis assay was carried out with acridine orange/ethidium bromide (AO/EB) staining methods. The studies on the mechanism of photocleavage demonstrate that superoxide anion radical (O(2)(-)) and singlet oxygen ((1)O(2)) may play an important role.

Synthesis, characterization, DNA interaction, antioxidant and anticancer activity studies of ruthenium(II) polypyridyl complexes.

Two new Ru(II) polypyridyl complexes [Ru(phen)₂(adppz)](ClO₄)₂ (1) and [Ru(dip)₂(adppz)](ClO₄)₂ (2) have been synthesized and characterized. The DNA-binding constants were determined to be 6.54 ± 0.42 × 10(5) and 7.65 ± 0.20 × 10(5)M(-1) for complexes 1 and 2. DNA binding experiments indicated that complexes 1 and 2 interact with DNA through intercalative mode. Antioxidant activity shows that the complexes have significant hydroxyl radical scavenging activity. Cytotoxic activities suggest that the complex 2 exhibits higher cytotoxic activity against BEL-7402, MG-63 and SKBR-3 cells than complex 1 under identical conditions. Complexes 1 and 2 can induce apoptosis of BEl-7402 cells. We have identified several cellular mechanisms induced by 1 and 2 in BEL-7402 cells, including the level detection of ROS, activation of procaspase 3, caspase 7, the expression of antiapoptotic proteins Bcl-x, Bcl-2, proapoptotic proteins Bad, Bax, Bid and cell cycle arrest. Thus, complexes 1 and 2 inhibit growth of BEL-7402 cells through induction of apoptotic cell death, enhancement of ROS levels and S-phase and G0/G1 cell cycle arrest. Further investigations have shown that complex 2 induces apoptosis by regulating the expression of Bcl-2 family proteins.

Ruthenium(II) complexes: synthesis, cytotoxicity in vitro, apoptosis, DNA-binding, photocleavage, and antioxidant activity studies

Two new ruthenium(II) complexes, [Ru(dmp)2(APIP)](ClO4)2 (1) (APIP = 2-(2-aminophenylimidazo[4,5-f][1,10]phenanthroline), dmp = 2,9-dimethyl-1,10-phenanthroline) and [Ru(dmp)2(HAPIP)](ClO4)2 (2) (HAPIP = 2-(2-hydroxyl-5-aminophenyl)imidazo[4,5-f][1,10]phenanthroline), were synthesized and characterized. The DNA-binding properties of these complexes were investigated by absorption titration, viscosity measurements, and photoactivated cleavage. The DNA-binding constants for 1 and 2 have been determined to be 2.3 (± 0.3) × 104 (mol L−1)−1 and 3.3 (± 0.4) × 104 (mol L−1)−1. The results indicate that 1 and 2 interact with DNA through intercalative mode. The cytotoxicities of 1 and 2 were assessed against BEL-7402, HepG-2 and MCF-7 cell lines using standard MTT assay. The apoptosis induced by these complexes was studied with the acridine orange/ethidium bromide staining method. The antioxidant activity on hydroxyl radical was also investigated.

Ruthenium(II) complexes: structure, DNA-binding, photocleavage, antioxidant activity, and theoretical studies

Two triazine-containing ruthenium(II) complexes, [Ru(dmb)2(pdpt)](ClO4)2 (dmb = 4,4′-dimethyl-2,2′-bipyridine, pdpt = 3-(pyridine-2-yl)-5,6-diphenyl-as-triazine) (1) and [Ru(dmb)2(pdtp)](ClO4)2 (pdtp = 3-(pyridine-2-yl)-as-triazino[5,6-f]phenanthrene) (2), were synthesized and characterized by elemental analysis, ES-MS, 1H NMR, UV-Vis spectra, and cyclic voltammetry; the crystal structure of 2 was determined by X-ray diffraction. DNA-binding behaviors of both complexes were studied by absorption titration, thermal denaturation, and viscosity measurements. The photoactivated DNA cleavage of plasmid pBR322 in the presence of 1 and 2 was explored through gel electrophoresis. Antioxidant activities of the two complexes against hydroxyl radical (•OH) were also investigated. The results indicate that the DNA-binding affinity of 2 is much greater than that of 1, and that 2 binds to calf thymus DNA by intercalation, but 1 binds in partial intercalation, with π–π stacking on the DNA surface. Experimental findings made through analysis of the CV, absorption spectra, X-ray crystal structure, and the DNA-binding properties were compared with those of theoretical studies using density functional calculations.

Cytotoxicity, Apoptosis, Cellular Uptake, Cell Cycle Arrest, Photocleavage, and Antioxidant Activity of 1, 10-Phenanthroline Ruthenium(II) Complexes

Two new ruthenium(II) complexes, [Ru(phen)2(DNPIP)](ClO4)2 (1) and [Ru(phen)2(DAPIP)](ClO4)2 (2), were synthesized and characterized. The DNA-binding properties of these complexes were investigated using UV/vis absorption titration, viscosity measurements, thermal denaturation, and photoactivated cleavage. The DNA binding constants for complexes 1 and 2 are 2.63 ± 0.25×10(5) M(-1) (s=2.45) and 1.51±0.18×10(5) M(-1) (s=1.34). The results indicated that these complexes interacted with DNA through the intercalative mode. The cytotoxicity in vitro of complexes 1 and 2 were assessed against BEL-7402, HepG-2, and MCF-7 cell lines by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was studied with the acridine orange/ethidium bromide staining method. The antiproliferative mechanism was explored with flow cytometry. Cellular uptake studies showed that complexes 1 and 2 can enter into the cytoplasm and accumulate in the nuclei. Cell cycle arrest and antioxidant activity were also investigated.

Synthesis, characterization, cellular uptake, apoptosis, cytotoxicity, dna-binding, and antioxidant activity studies of ruthenium(II) complexes.

Two new ruthenium(II) polypyridyl complexes [Ru(dmb)2(HECIP)](ClO4)2 (1) (HECIP = N-ethyl-4-[(1,10)-phenanthroline(5,6-f)imidazol-2-yl]carbazole, dmb = 4,4’-dimethyl-2,2’-bipyridine) and [Ru(dmp)2(HECIP)](ClO4)2 (2) (dmp = 2,9-dimethyl-1,10-phenanthroline) have been synthesized and characterized. The DNA-binding behaviors of the two complexes were investigated by absorption spectra, viscosity measurements, and photoactivated cleavage. The DNA-binding constants for complexes 1 and 2 were determined to be 8.03 (± 0.12) × 104 M−1 (s = 1.62) and 2.97 (± 0.15) × 104 M−1 (s = 1.82), respectively. The results suggest that these complexes interact with DNA through intercalative mode. The photocleavage of pBR322 DNA by Ru(II) complexes was investigated. The cytotoxicity of complexes 1 and 2 has been evaluated by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide)] method. Complex 1 shows higher anticancer potency than 2 against the four tumor cell lines. Apoptosis and cellular uptake were investigated. The antioxidant activities of the ligand and these complexes were also performed.

Cytotoxicity, cellular uptake, cell cycle arrest, apoptosis, reactive oxygen species and DNA-binding studies of ruthenium(II) complexes

Three ruthenium(II) polypyridyl complexes [Ru(dmb)2(dadppz)]2+1, [Ru(bpy)2(dadppz)]2+2 and [Ru(phen)2(dadppz)]2+3 were synthesized and characterized by elemental analysis, ES-MS, 1H NMR and 13C NMR. Their DNA-binding behaviors were investigated by absorption titration, fluorescence spectroscopy and viscosity measurements. Cytotoxicity in vitro, apoptosis, cell cycle arrest, cellular uptake and reactive oxygen species assays were performed. The complexes were found to show moderate DNA-binding affinities and high cytotoxicities toward A549, BEL-7402, MG-63 and SKBR-3 cell lines. These complexes can effectively induce apoptosis of BEL-7402. In cell cycle assays, the complexes induced S-phase arrest on BEL-7402 cells and G0/G1-phase arrest on SKBR-3 cells. The DNA-binding experiments showed that the three complexes interact with CT-DNA through an intercalative mode.

Cytotoxicity, apoptosis, interaction with DNA, cellular uptake, and cell cycle arrest of ruthenium(II) polypyridyl complexes containing 4,4′-dimethyl-2,2′-bipyridine as ancillary ligand

Two new ruthenium(II) polypyridyl complexes, [Ru(dmb)2(DNPIP)](ClO4)2 (1) (DNPIP = 2-(2,4-dinitrophenyl)imidazo[4,5-f][1,10]phenanthroline, dmb = 4,4′-dimethyl-2,2′-bipyridine) and [Ru(dmb)2(DAPIP)](ClO4)2 (2) (DAPIP = 2-(2,4-diaminophenyl)imidazo[4,5f][1,10]phenanthroline), were synthesized and characterized. The DNA-binding behaviors of these complexes have been studied by UV-Vis absorption titration, viscosity measurements, and photocleavage. The DNA-binding constants are 7.39 (±0.16) × 104 (s = 2.68) and 2.73 (±0.16) × 104 (mol L−1)−1 (s = 0.64) for 1 and 2, respectively. Their evaluation as cytotoxic agents on different cancer cell lines was investigated with IC50 values of 59.5, 51.3, and 70.3 µmol L−1 for 1, >100, 87.9, and 77.9 µmol L−1 for 2 against BEL-7402, HepG-2, and MCF-7 cells, respectively. Complex 1 is more active than 2 against selected cancer cell lines. The apoptosis induced by these complexes was studied. Cellular uptake showed that these complexes could enter into the cytoplasm and accumulate in the nuclei. The cell cycle arrest and antioxidant activity against hydroxyl radicals were also investigated.

Synthesis, DNA-binding, photocleavage, cytotoxicity, and apoptosis studies of ruthenium(II) complexes containing 3,6-dimethyldipyrido[3,2-a:2′,3′-c]phenazine

Two new ruthenium(II) polypyridyl complexes, [Ru(bpy)2(DMDPPZ)](ClO4)2 (1) (bpy = 2,2′-bipyridine, DMDPPZ = 3,6-dimethyldipyrido[3,2-a:2′,3′-c]phenazine) and [Ru(dmb)2(DMDPPZ)](ClO4)2 (2) (dmb = 4,4′-dimethyl-2,2′-bipyridine), have been synthesized and their DNA-binding, photoinduced DNA cleavage, and cell cytotoxicity are studied. The complexes show good binding to calf thymus DNA in the order: 1 > 2. Both complexes exhibit efficient DNA cleavage upon irradiation via a mechanistic pathway involving formation of singlet oxygen as the reactive species. The cytotoxic activity of 1 and 2 was tested by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) method. These complexes effectively inhibit the proliferation of tumor cells. The antioxidant activity against hydroxyl radical (•OH) was also explored.

Bis(2,9-dimethyl-1,10-phenanthroline-κ2N,N′)(10,11,12,13-tetra­hydro­dipyrido[3,2-a:2′,3′-c]phenazine-κ2N4,N5)ruthenium(II) bis­(perchlorate) dihydrate

The title compound, [Ru(C14H12N2)2(C18H14N4)](ClO4)2·2H2O, consists of an RuII complex cation, two perchlorate anions and two uncoordinated water molecules. The RuII ion is chelated by a 10,11,12,13-tetrahydrodipyrido[3,2-a:2′,3′-c]phenazine ligand and two 2,9-dimethyl-1,10-phenanthroline ligands in a distorted octahedral geometry. The two uncoordinated water molecules are disordered over five positions, with an occupancy factor of about 0.4 for each site. A supramolecular structure is formed by weak π–π interactions between neighbouring molecules, with centroid–centroid distances of 3.618 (2) and 3.749 (2) Å.