A newly synthesized nickel chelate can selectively target and overcome multidrug resistance in cancer through redox imbalance both in vivo and in vitro.

Induction of undesired toxicity and emergence of multidrug resistance (MDR) are the major obstacles for cancer treatment. Moreover, aggressive cancers are less sensitive towards existing chemotherapeutics. Therefore, selective targeting of cancers without inducing undesired side effects and designing proper strategies to overcome MDR has utmost importance in modern chemotherapy. Previously we revealed the anticancer properties of some transition metal chelates of Schiff base, but the effectiveness of nickel complex is still unrevealed. Herein, we synthesized and characterized a Schiff base nickel chelate, nickel-(II) N-(2-hydroxyacetophenone) glycinate (NiNG), through different spectroscopic means. NiNG proves to be a broad spectrum anticancer agent with considerable efficacy to overcome MDR in cancer. Antiproliferative effects of NiNG was evaluated using drug-resistant (CEM/ADR5000; NIH-MDR-G185; EAC/Dox), drug-sensitive aggressive (Hct116; CCRF-CEM; EAC/S) and normal (NIH-3T3) cells that reveal the selective nature of NiNG towards drug resistant and sensitive cancer cells without inducing any significant toxicity in normal cells. Moreover, NiNG involves reactive oxygen species (ROS)-mediated redox imbalance for induction of caspase 3-dependent apoptosis in aggressive drug-sensitive Hct116 and drug-resistant NIH-MDR-G185 cells through disruption of mitochondrial membrane potential. Moreover, intraperitoneal (i.p.) application of NiNG at non-toxic doses caused significant increase in the life-span of Swiss albino mice bearing sensitive and doxorubicin-resistant subline of Ehrlich ascites carcinoma cells. It is noteworthy that, in vitro NiNG can only overcome P-glycoprotein-mediated MDR while in vivo NiNG can overcome MRP1-mediated MDR in cancer. Therefore, NiNG has therapeutic potential to target and overcome MDR in cancer.

Induction of intrinsic and extrinsic apoptosis through oxidative stress in drug-resistant cancer by a newly synthesized Schiff base copper chelate.

Multidrug resistance (MDR) in cancer represents a variety of strategies employed by tumor cells to evade the beneficial cytotoxic effects of structurally different anticancer drugs and thus confers impediments to the successful treatment of cancers. Efflux of drugs by MDR protein-1, functional P-glycoprotein and elevated level of reduced glutathione confer resistance to cell death or apoptosis and thus provide a possible therapeutic target for overcoming MDR in cancer. Previously, we reported that a Schiff base ligand, potassium-N-(2-hydroxy 3-methoxy-benzaldehyde)-alaninate (PHMBA) overcomes MDR in both in vivo and in vitro by targeting intrinsic apoptotic/necrotic pathway through induction of reactive oxygen species (ROS). The present study describes the synthesis and spectroscopic characterization of a copper chelate of Schiff base, viz., copper (II)-N-(2-hydroxy-3-methoxy-benzaldehyde)-alaninate (CuPHMBA) and the underlying mechanism of cell death induced by CuPHMBA in vitro. CuPHMBA kills both the drug-resistant and sensitive cell types irrespective of their drug resistance phenotype. The cell death induced by CuPHMBA follows apoptotic pathway and moreover, the cell death is associated with intrinsic mitochondrial and extrinsic receptor-mediated pathways. Oxidative stress plays a pivotal role in the process as proved by the fact that antioxidant enzyme; polyethylene glycol conjugated-catalase completely blocked CuPHMBA-induced ROS generation and abrogated cell death. To summarize, the present work provides a compelling rationale for the future clinical use of CuPHMBA, a redox active copper chelate in the treatment of cancer patients, irrespective of their drug-resistance status.

In vitro and in vivo Anticancer Effects of a Novel 9-Phenyldibenzo[a,c]phenazin-9-ium Cation and Its Ligands.

BACKGROUND: Multidrug resistance (MDR) is a major problem in cancer treatment. Cu complexes possess the ability to overcome MDR in cancer. Therefore, the search for new Cu complexes is of great clinical significance and we address the anticancer effects of a previously synthesized novel 9-phenyldibenzo[a,c]phenazin-9-ium cation [1(+)] as [1] [CuCl2] and as [1] [I]. METHODS: The existence of the monovalent Cu(I) in [1] [CuCl2] was proven by electron paramagnetic resonance (EPR) studies and in vivo anticancer effects were studied in animals. RESULTS: The monovalent nature of the Cu ion in [1] [CuCl2] was determined through EPR. The mean survival time of mice bearing doxorubicin-resistant Ehrlich ascites carcinoma cells is longer when [1] [I] is injected intraperitoneally whereas [1] [CuCl2] does not significantly increase the median survival in tumor-bearing mice. Compounds do not follow the immunomodulatory route and only [1] [I] shows cytotoxic activity in both MDR and drug-sensitive leukemia cell lines. CONCLUSION: An organic iodide complex rather than a cupric complex possesses direct cytotoxic potential.

Asymmetric cleavage of 2,2'-pyridil to a picolinic acid anion radical coordinated to ruthenium(II): splitting of water to hydrogen.

The Ru(II)-H and water promoted asymmetric cleavage of 2,2'-pyridil to pyridine-2-carbaldehyde and unprecedented picolinic acid anion radical (PyCOOH(-)˙) complexes, which in solution produce H2 gas and diamagnetic picolinate complexes of ruthenium(II) in moderate yields, is reported.

9,10-phenanthrenesemiquinone radical complexes of ruthenium(III), osmium(III) and rhodium(III) and redox series.

Reactions of 9,10-phenanthrenequinone (PQ) in toluene with [M(II)(PPh3)3X2] at 298 K afford green complexes, trans-[M(PQ)(PPh3)2X2] (M = Ru, X = Cl, 1; M = Os, X = Br, 2) in moderate yields. Reaction of anhydrous RhCl3 with PQ and PPh3 in boiling ethanol affords the dark brown paramagnetic complex, cis-[Rh(PQ)(PPh3)2Cl2] (3) in good yields. Diffusion of iodine solution in n-hexane to the trans-[Os(PQ) (PPh3)2(CO)(Br)] solution in CH2Cl2 generates the crystals of trans-[Os(PQ)(PPh3)2(CO)(Br)](+)I3(-), (4(+))I3(-)), in lower yields. Single crystal X-ray structure determinations of 1·2toluene, 2·CH2Cl2 and 4(+)I3(-), UV-vis/NIR absorption spectra, EPR spectra of 3, electrochemical activities and DFT calculations on 1, 2, trans-[Ru(PQ)(PMe3)2Cl2] (1Me), trans-[Os(PQ)(PMe3)2Br2] (2Me), cis-[Rh(PQ)(PMe3)2Cl2] (3Me) and their oxidized and reduced analogues including trans-[Os(PQ)(PMe3)2(CO)(Br)](+) (4Me(+)) substantiated that 1-3 are the 9,10-phenanthrenesemiquinone radical (PQ(˙-)) complexes of ruthenium(III), osmium(III) and rhodium(III) and are defined as trans/cis-[M(III)(PQ(˙-))(PPh3)2X2] with a minor contribution of the resonance form trans/cis-[M(II)(PQ)(PPh3)2X2]. Two comparatively longer C-O (1.286(4) Å) and the shorter C-C lengths (1.415(7) Å) of the OO-chelate of 1·2toluene and 2·CH2Cl2 and the isotropic fluid solution EPR signal at g = 1.999 of 3 are consistent with the existence of the reduced PQ(˙-) ligand in 1-3 complexes. Anisotropic EPR spectra of the frozen glasses (g11 = g22 = 2.0046 and g33 = 1.9874) and solids (g11 = g22 = 2.005 and g33 = 1.987) instigate the contribution of the resonance form, cis-[Rh(II)(PQ)(PPh3)2Cl2] in 3. DFT calculations established that the closed shell singlet (CSS) solutions of 1Me and 2Me are unstable due to open shell singlet (OSS) perturbation. However, the broken symmetry (BS) (1,1) Ms = 0 solutions of 1Me and 2Me are respectively 22.6 and 24.2 kJ mole(-1) lower in energy and reproduced the experimental bond parameters well prompting the coordination of PQ(˙-) to the M(III) ions. The comparatively shorter C-O lengths, 1.268(4) and 1.266(5) Å and the longer C-C length, 1.466(6) Å, are consistent with the PQ chelation to osmium(II) ion in 4(+). The reversible anodic waves at 0.22, 0.22, and 0.18 V of 1-3, referenced by the Fc(+)/Fc couple, are assigned to the PQ(˙-)/PQ couple forming PQ complexes as trans/cis-[M(III)(PQ)(PPh3)2X2](+) while the cathodic waves at -0.92 and -0.89 V of 2 and 3 are due to formations of PQ(2-) complexes as trans-[M(III)(PQ(2-))(PPh3)2X2](-). 1 displays two overlapping cathodic waves at -0.72(89), -1.0(120) V. EPR spectrum of the frozen glass of 1(-) along with DFT calculations detected the contribution of both the valence tautomers, trans-[Ru(III)(PQ(2-))(PPh3)2Cl2](-) (g1 = g2 = 2.456; g3 = 1.983) and trans-[Ru(II)(PQ(˙-))(PPh3)2X2](-) (g(iso) = 1.999) in the anion. The characteristic lower energy absorption bands of 1 and 2 at 700 nm were assigned to CSS-OSS perturbation MLCT those are absent in paramagnetic 3, 1(+), 2(+), 1(-), 2(-) and 4(+) complexes, investigated by spectro-electrochemical measurements and time dependent (TD) DFT calculations on 1Me, 2Me, 1Me(+) and 1Me(-).

Electronic structures of ruthenium and osmium complexes of 9,10-phenanthrenequinone.

The reaction of 9,10-phenanthrenequinone (PQ) with [M(II)(H)(CO)(X)(PPh(3))(3)] in boiling toluene leads to the homolytic cleavage of the M(II)-H bond, affording the paramagnetic trans-[M(PQ)(PPh(3))(2)(CO)X] (M = Ru, X = Cl, 1; M = Os, X = Br, 3) and cis-[M(PQ)(PPh(3))(2)(CO)X] (M = Ru, X = Cl, 2; M = Os, X = Br, 4) complexes. Single-crystal X-ray structure determinations of 1, 2·toluene, and 4·CH(2)Cl(2), EPR spectra, and density functional theory (DFT) calculations have substantiated that 1-4 are 9,10-phenanthrenesemiquinone radical (PQ(•-)) complexes of ruthenium(II) and osmium(II) and are defined as trans-[Ru(II)(PQ(•-))(PPh(3))(2)(CO)Cl] (1), cis-[Ru(II)(PQ(•-))(PPh(3))(2)(CO)Cl] (2), trans-[Os(II)(PQ(•-))(PPh(3))(2)(CO) Br] (3), and cis-[Os(II)(PQ(•-))(PPh(3))(2)(CO)Br] (4). Two comparatively longer C-O [average lengths: 1, 1.291(3) Å; 2·toluene, 1.281(5) Å; 4·CH(2)Cl(2), 1.300(8) Å] and shorter C-C lengths [1, 1.418(5) Å; 2·toluene, 1.439(6) Å; 4·CH(2)Cl(2), 1.434(9) Å] of the OO chelates are consistent with the presence of a reduced PQ(•-) ligand in 1-4. A minor contribution of the alternate resonance form, trans- or cis-[M(I)(PQ)(PPh(3))(2)(CO)X], of 1-4 has been predicted by the anisotropic X- and Q-band electron paramagnetic resonance spectra of the frozen glasses of the complexes at 25 K and unrestricted DFT calculations on 1, trans-[Ru(PQ)(PMe(3))(2)(CO)Cl] (5), cis-[Ru(PQ)(PMe(3))(2)(CO)Cl] (6), and cis-[Os(PQ)(PMe(3))(2)(CO)Br] (7). However, no thermodynamic equilibria between [M(II)(PQ(•-))(PPh(3))(2)(CO)X] and [M(I)(PQ)(PPh(3))(2)(CO)X] tautomers have been detected. 1-4 undergo one-electron oxidation at -0.06, -0.05, 0.03, and -0.03 V versus a ferrocenium/ferrocene, Fc(+)/Fc, couple because of the formation of PQ complexes as trans-[Ru(II)(PQ)(PPh(3))(2)(CO)Cl](+) (1(+)), cis-[Ru(II)(PQ)(PPh(3))(2)(CO)Cl](+) (2(+)), trans-[Os(II)(PQ)(PPh(3))(2)(CO)Br](+) (3(+)), and cis-[Os(II)(PQ)(PPh(3))(2)(CO)Br](+) (4(+)). The trans isomers 1 and 3 also undergo one-electron reduction at -1.11 and -0.96 V, forming PQ(2-) complexes trans-[Ru(II)(PQ(2-))(PPh(3))(2)(CO)Cl](-) (1(-)) and trans-[Os(II)(PQ(2-))(PPh(3))(2)(CO)Br](-) (3(-)). Oxidation of 1 by I(2) affords diamagnetic 1(+)I(3)(-) in low yields. Bond parameters of 1(+)I(3)(-) [C-O, 1.256(3) and 1.258(3) Å; C-C, 1.482(3) Å] are consistent with ligand oxidation, yielding a coordinated PQ ligand. Origins of UV-vis/near-IR absorption features of 1-4 and the electrogenerated species have been investigated by spectroelectrochemical measurements and time-dependent DFT calculations on 5, 6, 5(+), and 5(-).

Osazone anion radical complex of rhodium(III).

One electron paramagnetic parent osazone complex of rhodium of type trans-Rh(L(NHPh)H(2))(PPh(3))(2)Cl(2) (1), defined as an osazone anion radical complex of rhodium(III), trans-Rh(III)(L(NHPh)H(2)(•-))(PPh(3))(2)Cl(2), 1((t-RhL•)), with a minor contribution (∼2%) of rhodium(II) electromer, trans-Rh(II)(L(NHPh)H(2))(PPh(3))(2)Cl(2), 1((t-Rh•L)), and their nonradical congener, trans-[Rh(III)(L(NHPh)H(2))(PPh(3))(2)Cl(2)]I(3) ([t-1](+)I(3)(-)), have been isolated and are substantiated by spectra, bond parameters, and DFT calculations on equivalent soft complexes [Rh(L(NHPh)H(2))(PMe(3))(2)Cl(2)] (3) and [Rh(L(NHPh)H(2))(PMe(3))(2)Cl(2)](+) (3(+)). 1 is not stable in solution and decomposes to [t-1](+) and a new rhodium(I) osazone complex, [Rh(I)(L(NHPh)H(2))(PPh(3))Cl] (2). 1 absorbs strongly at 351 nm due to MLCT and LLCT, while [t-1](+) and 2 absorb moderately in the range of 300-450 nm, respectively, due to LMCT and MLCT elucidated by TD-DFT calculations on 3((t-RhL•)), [t-3](+), and Rh(I)(L(NHPh)H(2))(PMe(3))Cl (4). EPR spectra of solids at 295 and 77 K, and dichloromethane-toluene frozen glass at 77 K of 1 are similar with g = 1.991, while g = 2.002 for the solid at 25 K. The EPR signal of 1 in dichloromethane solution is weaker (g = 1.992). In cyclic voltammetry, 1 displays two irreversible one electron transfer waves at +0.13 and -1.22 V, with respect to Fc(+)/Fc coupling, due to oxidation of 1((t-RhL•)) to [t-1](+) at the anode and reduction of rhodium(III) to rhodium(II), i.e., [t-1](+) to electromeric 1((t-Rh•L)) at the cathode.

Unsymmetrical diimine complexes of iron(II) and manganese(II): synthesis, structure and photoluminescence of an isomer.

Two bis(unsymmetrical diimine) complexes of (L(NO(2))(ϕ1))(L(NO(2))(ϕ2))M(II)Cl(2) family with M = Fe and Mn, are reported (L(NO(2))(ϕ) = (E)-3-nitro-N-(pyridine-2-ylmethylene)aniline; ϕ = dihedral angle between the diimine unit including pyridine ring and the phenyl ring planes). Pure tcc-(L(NO2)(33.6))(L(NO2)(79.3))Fe(II)Cl(2)·0.5H(2)O (1) and tcc-(L(NO2)(32.0))(L(NO2)(79.4))Mn(II)Cl(2)·0.5H(2)O (2) isomers have been successfully isolated in high yields and characterized by elemental analyses, variable temperature magnetic susceptibility measurements, IR, mass, UV-vis and Mössbauer spectra including the single-crystal X-ray structure determinations that identified strong intermolecular non-bonding interactions in lattice (tcc refers to trans-cis-cis positions with respect to pyridine N-imine N-Cl donors). Geometries optimizations of all possible tcc, ttt, ctc, ccc and cct isomers of iron at the B3LYP/DFT level in gas-phase have shown that the tcc-isomer incorporating two non-equivalent ligands as in (L(NO(2))(42))(L(NO(2))(61))Fe(II)Cl(2), 1 (g), is stabilized by 6-20 kJ mol(-1) compared to other isomers where two ligands are equivalent. The frozen methanol glasses of 1 and 2 are luminescent at 77 K (1: λ(ext) = 370, λ(em) = 521 nm, χ(2) = 1.3, τ(avg) = 0.57 ns; 2: λ(ext) = 368, λ(em) = 524 nm, χ(2) = 1.1, τ(avg) = 0.90 ns). The DFT calculations have identified four closely spaced localized π(*) orbitals comprising of two non-equivalent ligands as UPMOs. The features contrast the tcc-isomer of (L(ϕ))(2)Fe(II)Cl(2) (3), congener of 1 without -NO(2) substitution and non-emissive (bpy)(2)Fe(II)Cl(2) (4) where two ligands are equivalent. TD-DFT calculations have assigned intra-ligand (IL) and ligand to ligand charge transfer (LLCT) dominated excited states as the origin of luminescence of 1 and 2.