Photoactivatable Ruthenium Complexes Containing Minimal Straining Benzothiazolyl-1,2,3-triazole Chelators for Cancer Treatment.

Ruthenium(II) complexes containing diimine ligands have contributed to the development of agents for photoactivated chemotherapy. Several approaches have been used to obtain photolabile Ru(II) complexes. The two most explored have been the use of monodentate ligands and the incorporation of steric effects between the bidentate ligands and the Ru(II). However, the introduction of electronic effects in the ligands has been less explored. Herein, we report a systematic experimental, theoretical, and photocytotoxicity study of a novel series of Ru(II) complexes Ru1-Ru5 of general formula [Ru(phen)2(N∧N')]2+, where N∧N' are different minimal strained ligands based on the 1-aryl-4-benzothiazolyl-1,2,3-triazole (BTAT) scaffold, being CH3 (Ru1), F (Ru2), CF3 (Ru3), NO2 (Ru4), and N(CH3)2 (Ru5) substituents in the R4 of the phenyl ring. The complexes are stable in solution in the dark, but upon irradiation in water with blue light (λex = 465 nm, 4 mW/cm2) photoejection of the ligand BTAT was observed by HPLC-MS spectrometry and UV-vis spectroscopy, with t1/2 ranging from 4.5 to 14.15 min depending of the electronic properties of the corresponding BTAT, being Ru4 the less photolabile (the one containing the more electron withdrawing substituent, NO2). The properties of the ground state singlet and excited state triplet of Ru1-Ru5 have been explored using density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations. A mechanism for the photoejection of the BTAT ligand from the Ru complexes, in H2O, is proposed. Phototoxicity studies in A375 and HeLa human cancer cell lines showed that the new Ru BTAT complexes were strongly phototoxic. An enhancement of the emission intensity of HeLa cells treated with Ru5 was observed in response to increasing doses of light due to the photoejection of the BTAT ligand. These studies suggest that BTAT could serve as a photocleavable protecting group for the cytotoxic bis-aqua ruthenium warhead [Ru(phen)2(OH2)2]2+.

Ru(ii) photosensitizers competent for hypoxic cancers via green light activation.

A family of five heteroleptic complexes [Ru(C^N)(N^N)2][PF6] (HC^N = methyl 1-butyl-2-arylbenzimidazolecarboxylate; N^N = polypyridine) has been synthesized to act as biologically-compatible green light photosensitizers (PSs) with phototherapeutic indexes (PIs) up to higher than 700 under hypoxia (2% O2) in HeLa cancer cells under short time of irradiation.

Amino-Functionalized Mesoporous Silica Nanoparticle-Encapsulated Octahedral Organoruthenium Complex as an Efficient Platform for Combatting Cancer.

In the process of synthesis of a new drug, as important as the drug itself is the formulation used, because the same compound can present a very different efficacy depending on how it is administered. In this work, we demonstrate how the antitumor capacity of a new octahedral organoruthenium complex, [Ru(ppy-CHO)(phen)2][PF6] is affected by its encapsulation in different types of mesoporous silica nanoparticles. The interactions between the Ru complex and the silica matrix and how these interactions are affected at two different pHs (7.4 and 5.4, mimicking physiological and endolysosomal acidic conditions, respectively) have been studied. The encapsulation has also been shown to affect the induction of apoptosis and necrosis and progression of the cell cycle compared to the free drug. The encapsulation of the Ru complex in nanoparticles functionalized with amino groups produced very high anticancer activity in cancer cells in vitro, especially against U87 glioblastoma cells, favoring cellular internalization and significantly increasing the anticancer capacity of the initial non-encapsulated Ru complex.

New half-sandwich ruthenium(ii) complexes as proteosynthesis inhibitors in cancer cells.

Half-sandwich ruthenium(ii) complexes [(η6-p-cymene)Ru(C^N)-(X)]0/+ (X = Cl, py or 4-NMe2-py) containing a cyclometalated 2-ppy or 1-ppz with a non-coordinated CHO group as a handle for further functionalization have been synthesized to achieve selective cytotoxicity to cancer cells, the more potent compounds acting as proteosynthesis inhibitors; this is a new mode of action for half-sandwich metal complexes.

Structure, Spectra, and DFT Simulation of Nickel Benzazolate Complexes with Tris(2-aminoethyl)amine Ligand.

Benzazolate complexes of Ni(II), [Ni(pbz)(tren)]ClO4 (pbz = 2-(2'-hydroxyphenyl)-benzimidazole (pbm), 1, 2-(2'-hydroxyphenyl)-benzoxazole (pbx), 2, 2-(2'-hydroxyphenyl)-benzothiazole (pbt), 3; tren = tris(2-aminoethyl)amine), are prepared by self-assembly reaction and structurally characterized. Theoretical DFT simulations are carried out to reproduce the features of their crystal structures and their spectroscopic and photophysic properties. The three complexes are moderately luminescent at room temperature both in acetonitrile solution and in the solid state. The simulations indicate that the absorption spectrum is dominated by two well-defined transitions, and the electronic density concentrates in three MOs around the benzazole ligands. The Stokes shifts of the emission spectra of complexes 1-3 are determined by optimizing the electronic excited state.

Blocking and bridging ligands direct the structure and magnetic properties of dimers of pentacoordinate nickel(II).

Dinuclear pentacoordinate nickel(ii) complexes of the formula [(NiTp*)2(µ-L)] (Tp* = hydrotris(3,5-dimethylpyrazolyl)borate; L = oxalate (); oxamate (); oxamidate (); OC(4-Cl-C6H4N)C(4-Cl-C6H4N)O ()) and {[Ni(N3-mc)]2(µ-L)}(PF6)2 (N3-mc = 2,4,4-trimethyl-1,5,9-triazacyclododec-1-ene; L = oxalate (); oxamate ()) have been synthesized and spectroscopically characterized (IR, (1)H NMR). X-ray structures of show nickel(ii) in a square pyramidal geometry and different supramolecular interactions. Magnetic measurements for show strong antiferromagnetic interactions across the bridging ligand [: J = -36.8 cm(-1), g = 2.16; : J = -43.6 cm(-1), g = 2.12; : J = -51.1 cm(-1), g = 2.12; : J = -39.7 cm(-1), g = 2.18; : J = -35.4 cm(-1), g = 2.20; : J = -44.3 cm(-1), g = 2.18]. Magneto-structural correlations between the magnitude of the magnetic coupling and the different blocking ligands, the different bridging ligands, the distortion of the coordination environment of Ni(ii) and the planarity between the bridging ligand and the basal plane of the Ni(ii) environment have been established for all complexes.

Structure and spectroscopic properties of nickel benzazolate complexes with hydrotris(pyrazolyl)borate ligand.

The reaction of benzazole ligands 2-(2'-hydroxylphenyl)benzimidazole (Hpbm), 2-(2'-hydroxylphenyl)benzoxazole (Hpbx), and 2-(2'-hydroxylphenyl)benzothiazole (Hpbt), with [Ni(Tp*)(µ-OH)]2 (Tp* = hydrotris(3,5-dimethylpyrazolyl)borate), leads to pentacoordinate nickel complexes [Ni(Tp*)(pbz)] (pbz = pbm (1), pbx (2), pbt (3)). The structures of 1, 2, and 3 were determined by X-ray crystallography. The pentacoordinate nickel complexes have distorted trigonal bipyramidal geometries with Addison's τ parameter values of 0.63, 0.73, and 0.61 for 1, 2 and 3, respectively. The benzazolates are bonded in an η(2)(N,O) fashion to the nickel atoms. DFT calculations are carried out to optimize the structures of the three complexes giving a good agreement with the X-ray structures. The (1)H NMR spectra of complexes 1-3 exhibit sharp isotropically shifted signals. The complete assignment of these signals required an application of two-dimensional {(1)H-(1)H}-COSY techniques. The experimental absorption spectra of the three complexes in chloroform solution each show an intense absorption band in the ultraviolet region ca. 240 nm, followed by three less intense bands, the first two at ∼295 and ∼340 nm, and the last more disperse one, at wavelengths between 360 and 410 nm. The absorption spectra are simulated by TD-DFT and reproduce the main features of the experimental spectra well. The analysis of the electronic transitions by inspection of the frontier molecular orbitals and also the natural transition orbitals allowed us to characterize and assign the observed bands properly. The three complexes are moderately blue luminescent at room temperature, both in the solid state and in solution. Emission spectra at room temperature display broad structureless bands in chloroform solution at 460, 482, and 512 nm for complexes 1, 2 and 3, respectively, and structured emission in solid state with λmax values of 473, 486, and 516 nm. Complexes containing different donor atoms in the benzazole ligand are furthermore observed to give different luminescence responses in the presence of Zn(II), Cd(II), Hg(II), and Cu(II).

Novel saccharinate-bridged palladium complexes for efficient C-O bond activation displaying promising luminescence properties.

The synthesis of mono- and dinuclear cyclometallated palladium(II) complexes with deprotonated saccharinate ligands displaying different coordination modes is described. The new compounds were prepared by direct reaction between saccharine and the corresponding hydroxo-complexes [{Pd(µ-OH)(C^N)}(2)] (C^N = 2-(2-pyridyl)phenyl (Phpy) I; = 7,8-benzoquinolyl (Bzq) II), showing a general formula [{Pd(µ-sac)(C^N)}(2)] with saccharinate 1 displaying a bridging -NCO-coordination mode. Bridge splitting with neutral ligands (L = pyridine (py) 2, quinoline (quinol) 3 or acridine (acrid) 4) yielded new mononuclear derivatives with saccharinate acting as an N-monodentated ligand. Structural characterization by X-ray diffraction of complexes I1, I2 and II2 confirmed the proposed formulae. All complexes emit in the solution and solid state at room temperature. Emission features between 640-680 nm in the solid state for complexes I1 and II1 are significantly red-shifted if compared to the emission in solution. These broad emissions are consistent with the simultaneous presence of (3)ππ* and (3)MMLCT transitions indicating the existence of a strong intramolecular Pd-Pd ground state interaction. The dimeric complexes have also shown to catalyze Suzuki-Miyaura cross-coupling of coumaryl tosylate and aryl boronic acids under phosphine-free conditions. Initial studies suggest the involvement of palladium nanoparticles, which has been further investigated using mercury-drop test and poisoning experiments.

Synthesis and luminescence properties of cyclopalladated complexes with S

The direct reaction between the hydroxo-complexes [{Pd(µ-OH)(C^N)}(2)] and protonated S^N-donor ligands to yield new dinuclear cyclometallated palladium(ii) complexes containing -NCS- bridging heterocyclic thionates of general formula [{Pd(µ-N^S)(C^N)}(2)] (C^N = 2-(2-pyridyl)phenyl (Phpy) I; = 7,8-benzoquinolyl (Bzq) II; N^S = pyrimidine-2-thionate (Spym) 1, benzoimidazolidine-2-thionate (Sbimid) 2, 1-methylimidazoline-2 thionate (Smeimid) 3) is described. The related mononuclear complexes [Pd(N^S)(C^N)] N^S = 2-aminothiophenolate (Atph) 4) were prepared in a similar way. Photophysical properties were investigated together with those of complexes with related ligands pyridin-2-thionate (Spy) 5 and pyrrole-2-carboxaldehydate (2-pcal) 6. All the compounds absorb intensely below 300 nm via(1)LC transitions located in Bzq or Phpy ligands, and display additional low energy absorptions of mixed (1)MLCT-(1)LC character. In the solid state diffuse reflectance UV-vis spectra, the differences are notable for dinuclear complexes. The complexes under study are quite unusual in terms of luminescence behaviour, since most of them are emissive in solution at room temperature and all display intense emissions in frozen CHCl(3) solution, but also in the solid state at 298 and 77 K. Emission quantum yields are in the range 2.52-0.14%, similar to that of related complexes. Structural characterisation by X-ray diffraction of complexes II3 and II6 confirmed the proposed formula.

Crystal structures and magnetic properties of nickel complexes with hydrotris(pyrazolyl)borate ligand and double bridged by phosphate esters.

The reaction between [NiTp*(µ-OH)]2 (Tp* = hydrotris(3,5-dimethylpyrazolyl)borate) and (RO)2P(O)OH (R = Et, Bu, 4-NO2-Ph) affords the dinuclear nickel phosphates [NiTp*(µ-O2P(OR)2)]2 (R = Et (1), Bu (2), 4-NO2-Ph (3)), which have been studied by spectroscopic methods (IR, UV-vis, and (1)H NMR). In chloroform solution, those complexes exhibit isotropically shifted (1)H NMR resonances. Their molecular structures reveal that they all have an eight-membered Ni2O4P2 ring which possesses two nickel centers bridged to each other by two isobidentate phosphate ligands. Magnetic studies on 1-3 and other similar complexes (4 and 5) reveal antiferromagnetic behavior at low temperatures as well as an interesting correlation between calculated D values and the planarity of eight-membered Ni2O4P2 rings.

Luminescence of five-coordinated nickel(ii) complexes with substituted-8-hydroxyquinolines and macrocyclic ligands.

A series of heteroleptic quinolinolate pentacoordinated nickel(ii) complexes, [Ni(mcN(3))(R(1),R(2),R(3)-8-hq)](PF(6)), were synthesized and characterized by spectroscopic methods. Single-crystal X-ray diffraction studies for [(Me(3)-mcN(3))Ni(N,O-2-CN-8-hq)][PF(6)] (6a), [(Me(4)-mcN(3))Ni(N,O-8-hq)][PF(6)] (2b) and [(Me(4)-mcN(3))Ni(N,O-5,7-I(2)-8-hq)][PF(6)] (5b) indicate that these complexes consist of a square-pyramidal ligand arrangement containing one chelating quinolinolate and one macrocyclic ligand (mcN(3)). Variation of the substituents on quinolinolate ligands imposes obvious electronic or structural effects on the nickel atom. These chromophores absorb moderately in the visible region and emit in the yellowish-green spectral region from a quinolinolate-centered intraligand charge-transfer excited state. The emission maxima are in the range 520-548 nm, with quantum yields between 0.11 and 1.63%, in deoxygenated organic solvents at room temperature. TD-DFT calculations allow exploration of the photophysical properties of complex [(Me(4)-mcN(3))Ni(N,O-8-hq)][PF(6)] and reveal the influence of the quinolinolate ligand on the HOMO/LUMO energies and oscillator strengths.

Mono- and bidentate imidates of five-coordinate nickel(II) with macrocyclic ligands: spectroscopic and photophysical properties.

The hydroxo-complexes [Ni(2)(mcN(3))(2)(mu-OH)](2)(PF(6))(2)] [mcN(3) = 2,4,4-trimethyl-1,5,9-triazacyclododec-1-ene (Me(3)-mcN(3)) or 2,4,4,9-tetramethyl-1,5,9-triazacyclododec-1-ene (Me(4)-mcN(3))] react with imides (Him) in 1 : 2 (succinimide, glutarimide, saccharine and 1,8-naphthalimide) or 1 : 1 (pyromellitic diimide) molar ratio, leading to the formation of the imidate complexes: [Ni(mcN(3))(H(2)O)(Im)](+) (Im = succi, gluti, sac), [Ni(mcN(3))(naphthi)](+) and [Ni(mcN(3))(H(2)O)](2)(mu-pyrdi)](2+). The single crystal structures of [Ni(Me(3)-mcN(3))(H(2)O)(sac)](PF(6)) (3a) and [Ni(Me(4)-mcN(3))(H(2)O)(sac)](sac) (3b) show that, in 3a, sac exhibits a N-monodentate coordination mode, while in 3b the coordination is through oxygen. X-Ray structure of [Ni(Me(4)-mcN(3))(naphthi)](PF(6)) (4b) shows N,O-bonded 1,8-naphthalimidate ligand. The VT (1)H NMR study, carried out on this complex, suggests that the rotation around the Ni-N bond is hindered by ca. 11.6 kcal mol(-1). These species exhibit blue luminescence which arises from a mixed MLCT and LC excited state, and these properties may be useful for structural predictions in the solid state of complexes for which crystal structures have not been established.

Five-coordinate nickel(II) complexes with carboxylate anions and derivatives of 1,5,9-triazacyclododec-1-ene: structural and 1H NMR spectroscopic studies.

The hydroxo complexes [Ni2(mcN3)2(mu-OH)2]2(PF6)2[mcN3 = 2,4,4-trimethyl-1,5,9-triazacyclododec-1-ene (Me3-mcN3) or 2,4,4,9-tetramethyl-1,5,9-triazacyclododec-1-ene (Me4-mcN3)] react with the corresponding carboxylic acid [HA = benzoic (Hbz), salicylic (Hsal) or acetylsalicylic (Hacsal) acid] to give five-coordinate nickel(II) complexes of the type [Ni(mcN3)(A)](PF6). The complexes have been studied by spectroscopic methods (IR, UV-Vis and 1H NMR). In acetone solution they exhibit isotropically shifted 1H NMR resonances. The full assignment of these resonances has been made using one- and two-dimensional 1H NMR techniques. The single-crystal structures of [Ni(Me4-mcN3)(bz)](PF6), [Ni(Me4-mcN3)(sal)](PF6) and[Ni(Me4-mcN3)(acsal)](PF6) have been established by X-ray diffraction.

Pentacoordinate nickel(II) complexes double bridged by phosphate ester or phosphinate ligands: spectroscopic, structural, kinetic, and magnetic studies.

The bis(phosphatediester)-bridged complexes [[Ni([12]aneN(3))(mu-O(2)P(OR)(2))](2)](PF(6))(2) [[12]aneN(3)=Me(3)[12]aneN(3), 2,4,4-trimethyl-1,5,9-triazacyclododec-1-ene; R=Me (1), Bu (2), Ph (3), Ph-4-NO(2) (4); [12]aneN(3)=Me(4)[12]aneN(3), 2,4,4,9-tetramethyl-1,5,9-triazacyclododec-1-ene; R=Me (5), Bu (6), Ph (7), Ph-4-NO(2) (8)] were prepared by hydrolysis of the phosphate triester with the hydroxo complex [[Ni([12]aneN(3))(mu-OH)](2)](PF(6))(2) or by acid-base reaction of the dialkyl or diaryl phosphoric acid and the above hydroxo complex. The acid-base reaction was also used to synthesise the phosphinate-bridged complexes [[Ni([12]aneN(3))(mu-O(2)PR(2))](2)](PF(6))(2) [[12]aneN(3)=Me(3)[12]aneN(3), R=Me (9), Ph (10); [12]aneN(3)=Me(4)[12]aneN(3), R=Me (11), Ph (12)]. The molecular structures of complexes 2, 3 and 12 were established by single crystal X-ray diffraction studies. The eight-membered rings defined by the nickel atoms and the bridging ligands show distorted twist-boat, chair and boat-boat conformations in 2, 3 and 12, respectively. The experimental susceptibility data for compounds 2, 3 and 12 were fitted by least-squares methods to the analytical expression given by Ginsberg. The best fit was obtained with values of J=-0.11 cm(-1), D=-9.5 cm(-1) and g=2.20 for 2; J=-0.97 cm(-1), D=-9.3 cm(-1) and g=2.21 for 3; and J=-0.14 cm(-1), D=-11.9 cm(-1) and g=2.195 for 12. The magnetic-exchange pathways must involve the phosphate/phosphinate bridges, because these favour antiferromagnetic interactions. The observation of a higher exchange parameter for compound 3 is a consequence of a favourable disposition of the O-P-O bridges. The kinetics for the hydrolysis of TNP (tris(4-nitrophenyl)phosphate) with the dinuclear nickel(II) hydroxo complex [[Ni(Me(3)[12]aneN(3))(mu-OH)](2)](PF(6))(2) was studied by UV-visible spectroscopy. The proposed mechanism for TNP-promoted hydrolysis can be described as one-substrate/two-product, and can be fitted to a Michaelis-Menten equation.

Oxamidate-bridged dinuclear five-coordinate nickel(II) complexes: a magneto-structural study.

The preparation, spectroscopic characterization, and magnetic study of three new oxamidate-bridged nickel(II) dinuclear complexes of formulas ([Ni(Me3[12]aneN3)]2(mu-oa))(PF6)2 (1), ([Ni(Me3[12]aneN3)]2(mu-dmoa))(PF6)2 (2), and ([Ni(Me3[12]aneN3)]2(mu-dpoa))(PF6)2 (3) (Me3[12]aneN3 = 2,4,4-trimethyl-1,5,9-triazacyclododec-1-ene, oa = oxamidate, dmoa = N,N'-dimethyloxamidate, and dpoa = N,N'-diphenyloxamidate) are reported. The crystal structures of two of them (1 and 3) have been determined. 1 and 3 crystallize in the monoclinic system, space group P2(1)/c, with Z = 2 and a = 7.901(4) A, b = 13.597(6) A, c = 17.565(10) A, and beta = 96.46(4) degrees for 1 and a = 13.854(3) A, b = 17.469(4) A, c = 12.543(3) A, and beta = 116.22(3) degrees for 3. The structures of 1 and 3 consist of dinuclear ([Ni(Me3[12]aneN3)]2(mu-oa))2+ and ([Ni(Me3[12]aneN3)]2(mu-dpoa))2+ cations and hexafluorophosphate anions. Each nickel in 1-3 is five-coordinate, and the substitution of the hydrogen atom of the amidate nitrogen of 1 by a methyl (2) or a phenyl (3) group causes a significant modification of the stereochemistry of the nickel(II) ions from square pyramidal toward trigonal bipyramidal (tau values of 0.12 and 0.48 for 1 and 3, respectively). The NOESY spectrum of 3 has allowed us to achieve the assignment of the phenyl protons of the N,N'-diphenyloxamidate. The value of magnetic coupling between the two nickel(II) ions across the oxamidate bridge [J = -57.0 (oa, 1), -38.0 (dmoa, 2) and -30.5 cm(-1) (dpoa, 3)] is very sensitive to this stereochemical change, and its variation is explained on the basis of orbital considerations. DFT type calculations have been performed to analyze and substantiate the trend of the magnetic coupling in 1-3.