Bichromophoric ruthenium(II) bis-terpyridine-BODIPY based photosensitizers for cellular imaging and photodynamic therapy.

Two multichromophoric homoleptic ruthenium(II) complexes [Ru(tpy-BODIPY)2]Cl2 (complexes 1 and 2, tpy = 4-phenyl-2,2:6,2-terpyridine, BODIPY = boron-dipyrromethene) were prepared, characterized and their phototherapeutic activity and bioimaging properties were studied. The complexes having structural similarity differ only by a phenylethynyl linker, and its overall influence on their physicochemical and photobiological behavior was evaluated. The terpyridine-BODIPY ligand L1 was structurally characterized by X-ray crystallography. The complexes showed intense absorption near 500 nm (ε: ∼1.5 × 105 M-1 cm-1 in DMSO), have a high singlet oxygen quantum yield (ΦΔ: ∼0.6 in DMSO), and displayed low photobleaching thus making them suitable for PDT applications. The complexes showed high DNA binding affinity and induced DNA damage on light activation via multiple types of ROS production. Confocal laser scanning microscopy experiments revealed their incorporation in the cancer cells and complex 1 predominantly accumulated in lysosomes. The complexes displayed a significant PDT effect in cancerous cells with visible light activation with a high photocytotoxicity index (PI) value in HeLa cells. Both type-I and type-II photosensitization processes were involved in the PDT effect. The photodynamic action of complex 2 initiated cellular apoptosis. Finally, their diagnostic potential was evaluated against clinically relevant 3D multicellular tumor spheroids (MCTs).

Nickel(II)-Mediated Reversible Thiolate/Disulfide Conversion as a Mimic for a Key Step of the Catalytic Cycle of Methyl-Coenzyme†M Reductase.

According to the well-accepted mechanism, methyl-coenzyme M reductase (MCR) involves Ni-mediated thiolate-to-disulfide conversion that sustains its catalytic cycle of methane formation in the energy saving pathways of methanotrophic microbes. Model complexes that illustrate Ni-ion mediated reversible thiolate/disulfide transformation are unknown. In this paper we report the synthesis, crystal structure, spectroscopic properties and redox interconversions of a set of NiII complexes comprising a tridentate N2 S donor thiol and its analogous N4 S2 donor disulfide ligands. These complexes demonstrate reversible NiII -thiolate/NiII -disulfide (both bound and unbound disulfide-S to NiII ) transformations via thiyl and disulfide monoradical anions that resemble a primary step of MCR's catalytic cycle.

Ruthenium(II) Conjugates of Boron-Dipyrromethene and Biotin for Targeted Photodynamic Therapy in Red Light.

The ruthenium(II) complexes [RuCl(L1)(L3)]Cl (1), [RuCl(L1)(L4)]Cl (2), [RuCl(L2)(L4)]Cl (3), [RuCl(L1)(L5)]Cl (4), and [RuCl(L2)(L5)]Cl (5) of NNN-donor dipicolylamine (dpa) bases (L4, L5) having BODIPY (boron-dipyrromethene) moieties, NN-donor phenanthroline derivatives (L1, L2), and benzyldipicolylamine (bzdpa, L3) were prepared and characterized by spectroscopic techniques and their cellular localization/uptake and photocytotoxicity studied. Complex 1, as its PF6 salt (1a), has been structurally characterized with help of a single-crystal X-ray diffraction technique. It has a RuN5Cl core with the Cl bonded trans to the amine nitrogen atom of bzdpa. The complexes showed intense absorption spectral bands near 500 nm (ε ≈ 58000 M-1 cm-1) in 2 and 3 and 654 nm (ε ≈ 80000 M-1 cm-1) in 4 and 5 in 1/1 DMSO/DPBS (v/v). Complex 5 having biotin and PEGylated-disteryl BODIPY gave a singlet oxygen quantum yield (ΦΔ) of ∼0.65 in DMSO. Complex 5 exhibited remarkable PDT (photodynamic therapy) activity (IC50 ≈ 0.02 µM) with a photocytotoxicity index (PI) value of >5000 in red light of 600-720 nm in A549 cancer cells. The biotin-conjugated complexes showed better photocytotoxicity in comparison to nonbiotinylated analogues in A549 cells. The complexes displayed less toxicity in HPL1D normal cells in comparison to A549 cancer cells. The emissive BODIPY complexes 3 and 5 (ΦF ≈ 0.07 in DMSO) showed significant mitochondrial localization.

Mixed valence copper-sulfur clusters of highest nuclearity: a Cu8 wheel and a Cu16 nanoball.

Fully spin delocalized mixed valence copper-sulfur clusters, 1 and 2, supported by µ4-sulfido and NSthiol donor ligands are synthesized and characterized. Wheel shaped 1 consists of Cu2S2 units. The unprecedented nanoball 2 can be described as S@Cu4(tetrahedron)@O6(octahedron)@Cu12S12(cage) consisting of both Cu2S2 and (µ4-S)Cu4 units. The Cu2S2 and (µ4-S)Cu4 units resemble biological CuA and CuZ sites respectively.

Electron transfer mechanism of catalytic superoxide dismutation via Cu(ii/i) complexes: evidence of cupric-superoxo/-hydroperoxo species.

To understand the electron transfer mechanisms (outer versus inner sphere) of catalytic superoxide dismutation via a Cu(ii/i) redox couple such as occur in the enzyme copper-zinc superoxide dismutase, the Cu(ii/i) complexes [(L1)2Cu](ClO4)2·CH3CN, (1·CH3CN) and [(L1)2Cu](ClO4), (2) supported by a bis-N2Sthioether ligand, 2-pyridyl-N-(2'-methylthiophenyl)methyleneimine (L1) have been synthesized and structurally characterised. Both 1 and 2 display the same cyclic voltammogram (CV) featuring a quasireversible response at E1/2 = +0.33 V vs. SCE that falls in the SOD potential window of -0.04 V to +0.99 V. These complexes catalytically dismutate superoxide radicals at 298 K in aqueous medium (the IC50 for 1 is 2.15 µM). Electronic absorption spectra (233 K and 298 K), FTIR, ESI mass spectra, CV (233 K and 298 K) and DFT calculations collectively indicate formation of [(L1)2Cu(O2˙(-))](+), [(L1)2Cu(O2(2-))] and [(L1)2Cu(OOH(-))](+) species and help to elucidate the electron transfer mechanism for the SOD function of 1 and 2. Once O2˙(-) binds to Cu(II) (evident at 233 K), the first step of the catalytic cycle (Cu(II) + O2˙(-)→ Cu(I) + O2) does not follow but the second step (Cu(I) + O2˙(-) + 2H(+)→ H2O2 + Cu(II)) does follow. Therefore, the catalytic disproportionation of superoxide radicals via1 and 2 at 298 K indicates that the first and second steps of the catalytic cycle proceed through outer and inner sphere electron transfer mechanisms, respectively. Feasibility of the first step to occur in pure aprotic solvent (where 18-crown-6-ether is used to solubilise KO2) was tested and also supports the same notion of the electron transfer mechanisms as stated above.

Copper coordinated ligand thioether-S and NO2(-) oxidation: relevance to the CuM site of hydroxylases.

In order to gain insight into the coordination site and oxidative activity of the CuM site of hydroxylases such as peptidylglycine α-hydroxylating monooxygenase (PHM), dopamine ß-monooxygenase (DßM), and tyramine ß-monooxygenase (TßM), we have synthesized, characterized and studied the oxidation chemistry of copper complexes chelated by tridentate N2Sthioether, N2Osulfoxide or N2Osulfone donor sets. The ligands are those of N-2-methylthiophenyl-2'-pyridinecarboxamide (HL1), and the oxidized variants, N-2-methylsulfenatophenyl-2'-pyridinecarboxamide (HL1(SO)), and N-2-methylsulfinatophenyl-2'-pyridinecarboxamide (HL1(SO2)). Our studies afforded the complexes [(L1)Cu(II)(H2O)](ClO4)·H2O (1·H2O), {[(L1(SO))Cu(II)(CH3CN)](ClO4)}n (2), [(L1)Cu(II)(ONO)] (3), [(L1(SO))Cu(II)(ONO)]n (4), [(L1)Cu(II)(NO3)]n (5), [(L1(SO))Cu(II)(NO3)]n (6) and [(L1(SO2))Cu(II)(NO3)] (7). Complexes 1 and 3 were described in a previous publication (Inorg. Chem., 2013, 52, 11084). The X-ray crystal structures revealed either distorted octahedral (in 2, 4-6) or square-pyramidal (in 1, 3) coordination geometry around Cu(II) ions of the complexes. In the presence of H2O2, conversion of 1→2, 3-5→6 and 6→7 occurs quantitatively via oxidation of thioether-S and/or Cu(ii) coordinated NO2(-) ions. Thioether-S oxidation of L1 also occurs when [L1](-) is reacted with [Cu(I)(CH3CN)4](ClO4) in DMF under O2, albeit low in yield (20%). Oxidations of thioether-S and NO2(-) were monitored by UV-Vis spectroscopy. Recovery of the sulfur oxidized ligands from their metal complexes allowed for their characterization by elemental analysis, (1)H NMR, FTIR and mass spectrometry.

Hexacoordinate nickel(II)/(III) complexes that mimic the catalytic cycle of nickel superoxide dismutase.

A functional model complex of nickel superoxide dismutase (NiSOD) with a non-peptide ligand which mimics the full catalytic cycle of NiSOD is unknown. Similarly, it has not been fully elucidated whether NiSOD activity is a result of an outer- or inner-sphere electron-transfer mechanism. With this in mind, two octahedral nickel(II)/(III) complexes of a bis-tridentate N2 S donor carboxamide ligand, N-2-phenylthiophenyl-2'-pyridinecarboxamide (HL(Ph)), have been synthesized, structurally characterized, and their SOD activities examined. These complexes mimic the full catalytic cycle of NiSOD. Electrochemical experiments support an outer-sphere electron-transfer mechanism for their SOD activity.

Copper complexes relevant to the catalytic cycle of copper nitrite reductase: electrochemical detection of NO(g) evolution and flipping of NO2 binding mode upon Cu(II) → Cu(I) reduction.

Copper complexes of the deprotonated tridentate ligand, N-2-methylthiophenyl-2'-pyridinecarboxamide (HL1), were synthesized and characterized as part of our investigation into the reduction of copper(II) o-nitrito complexes into the related copper nitric oxide complexes and subsequent evolution of NO(g) such as occurs in the enzyme copper nitrite reductase. Our studies afforded the complexes [(L1)Cu(II)Cl]n (1), [(L1)Cu(II)(ONO)] (2), [(L1)Cu(II)(H2O)](ClO4)·H2O (3·H2O), [(L1)Cu(II)(CH3OH)](ClO4) (4), [(L1)Cu(II)(CH3CO2)]·H2O (5·H2O), and [Co(Cp)2][(L1)Cu(I)(NO2)(CH3CN)] (6). X-ray crystal structure determinations revealed distorted square-pyramidal coordination geometry around Cu(II) ion in 1-5. Substitution of the H2O of 3 by nitrite quantitatively forms 2, featuring the κ(2)-O,O binding mode of NO2(-) to Cu(II). Reduction of 2 generates two Cu(I) species, one with κ(1)-O and other with the κ(1)-N bonded NO2(-) group. The Cu(I) analogue of 2, compound 6, was synthesized. The FTIR spectrum of 6 reveals the presence of κ(1)-N bonded NO2(-). Constant potential electrolysis corresponding to Cu(II) → Cu(I) reduction of a CH3CN solution of 2 followed by reaction with acids, CH3CO2H or HClO4 generates 5 or 3, and NO(g), identified electrochemically. The isolated Cu(I) complex 6 independently evolves one equivalent of NO(g) upon reaction with acids. Production of NO(g) was confirmed by forming [Co(TPP)NO] in CH2Cl2 (λ(max) in CH2Cl2: 414 and 536 nm, ν(NO) = 1693 cm(-1)).

Shuttling of nickel oxidation states in N4S2 coordination geometry versus donor strength of tridentate N2S donor ligands.

Seven bis-Ni(II) complexes of a N(2)S donor set ligand have been synthesized and examined for their ability to stabilize Ni(0), Ni(I), Ni(II) and Ni(III) oxidation states. Compounds 1-5 consist of modifications of the pyridine ring of the tridentate Schiff base ligand, 2-pyridyl-N-(2'-methylthiophenyl)methyleneimine ((X)L1), where X = 6-H, 6-Me, 6-p-ClPh, 6-Br, 5-Br; compound 6 is the reduced amine form (L2); compound 7 is the amide analog (L3). The compounds are perchlorate salts except for 7, which is neutral. Complexes 1 and 3-7 have been structurally characterized. Their coordination geometry is distorted octahedral. In the case of 6, the tridentate ligand coordinates in a facial manner, whereas the remaining complexes display meridional coordination. Due to substitution of the pyridine ring of (X)L1, the Ni-N(py) distances for 1~5 < 3 < 4 increase and UV-vis λ(max) values corresponding to the (3)A(2g)(F)→(3)T(2g)(F) transition show an increasing trend 1~5 < 2 < 3 < 4. Cyclic voltammetry of 1-5 reveals two quasi-reversible reduction waves that correspond to Ni(II)→Ni(I) and Ni(I)→Ni(0) reduction. The E(1/2) for the Ni(II)/Ni(I) couple decreases as 1 > 2 > 3 > 4. Replacement of the central imine N donor in 1 by amine 6 or amide 7 N donors reveals that complex 6 in CH(3)CN exhibits an irreversible reductive response at E(pc) = -1.28 V, E(pa) = +0.25 V vs saturated calomel electrode (SCE). In contrast, complex 7 shows a reversible oxidation wave at E(1/2) = +0.84 V (ΔE(p) = 60 mV) that corresponds to Ni(II)→Ni(III). The electrochemically generated Ni(III) species, [(L3)(2)Ni(III)](+) is stable, showing a new UV-vis band at 470 nm. EPR measurements have also been carried out.