Ashis K. Patra

A thermally stable {FeNO}8 complex: properties and biological reactivity of reduced MNO systems

Reduced nitrogen oxide ligands such as NO−/HNO or nitroxyl participate in chemistry distinct from nitric oxide (NO). Nitroxyl has been proposed to form at heme centers to generate the Enemark–Feltham designated {FeNO}8 system. The synthesis of a thermally stable {FeNO}8 species namely, [Co(Cp*)2][Fe(LN4)(NO)] (3), housed in a heme-like ligand platform has been achieved by reduction of the corresponding {FeNO}7 complex, [Fe(LN4)(NO)] (1), with decamethylcobaltocene [Co(Cp*)2] in toluene. This complex readily reacts with metMb, resulting in formation of MbNO via reductive nitrosylation by the coordinated HNO/NO−, which can be inhibited with GSH. These results suggest that 3 could serve as a potential HNO therapeutic. Spectroscopic, theoretical, and structural comparisons are made to 1 and the {CoNO}8 complex, [Co(LN4)(NO)] (2), an isoelectronic analogue of 3.

Versatile Methodology Toward NiN2S2 Complexes as Nickel Superoxide Dismutase Models: Structure and Proton Affinity

Structural features of the reduced form of the nickel superoxide dismutase (Ni-SOD) active site have been modeled with asymmetric NiN(2)S(2) complexes (Et(4)N)[Ni(nmp)(SR)] (R = C(6)H(4)-p-Cl (2) and (S(t)Bu) (3)) obtained via S,S-bridge splitting of the dimeric metallosynthon, [Ni(2)(nmp)(2)] (1). Complexes 2 and 3 are irreversibly oxidized at potentials within the window needed for SOD activity, 236 and 75 mV versus Ag/AgCl, respectively. The exogenous thiolato-S in 2 and 3 serves as a proton acceptor, suggesting potential involvement of Cys6 in Ni-SOD for H(+) storage between SOD half reactions.

Stable eight-coordinate iron(III/II) complexes.

The chemistry of unusual coordination numbers of transition-metal complexes has been of interest because of their presence in biology and catalytic systems. Herein we describe a systematic and predictable approach toward isolation of stable eight-coordinate (8C) iron(III/II) systems. The 8C (S = 2; high-spin, HS) complex [Fe(L(N4))(2)](BF(4))(2) (1) has been synthesized and characterized, displaying a distorted square-antiprism structure. Complex 1 is a unique 8C iron complex that exhibits remarkable stability in solution under various unfavorable conditions. The E(1/2) value of 1 (0.430 V vs Ag/AgCl, MeCN) supports the Fe(II) oxidation state; however, the corresponding HS (S = 5/2) 8C Fe(III) analogue [Fe(L(N4))(2)](NO(3))(3) (3) has also been synthesized via the chemical oxidation of 1. The structural, spectroscopic, and theoretical descriptions of these 8C iron complexes are reported in this work.

Synthesis, properties, and reactivity of a series of non-heme {FeNO}(7/8) complexes: implications for Fe-nitroxyl coordination.

The biochemical properties of nitroxyl (HNO/NO(-)) are distinct from nitric oxide (NO). Metal centers, particularly Fe, appear as suitable sites of HNO activity, both for generation and targeting. Furthermore, reduced Fe-NO(-)/Fe-HNO or {FeNO}(8) (Enemark-Feltham notation) species offer unique bonding profiles that are of fundamental importance. Given the unique chemical properties of {FeNO}(8) systems, we describe herein the synthesis and properties of {FeNO}(7) and {FeNO}(8) non-heme complexes containing pyrrole donors that display heme-like properties, namely [Fe(LN(4)(R))(NO)] (R = C(6)H(4) or Ph for 3; and R = 4,5-Cl(2)C(6)H(2) or PhCl for 4) and K[Fe(LN(4)(R))(NO)] (R = Ph for 5; R = PhCl for 6). X-ray crystallography establishes that the Fe-N-O angle is ~155° for 3, which is atypical for low-spin square-pyramidal {FeNO}(7) species. Both 3 and 4 display ν(NO) at ~1700 cm(-1) in the IR and reversible diffusion-controlled cyclic voltammograms (CVs) (E(1/2)=~-1.20 V vs. Fc/Fc(+) (ferrocene/ferrocenium redox couple) in MeCN) suggesting that the {FeNO}(8) compounds 5 and 6 are stable on the CV timescale. Reduction of 3 and 4 with stoichiometric KC(8) provided the {FeNO}(8) compounds 5 and 6 in near quantitative yield, which were characterized by the shift in ν(NO) to 1667 and ~1580 cm(-1), respectively. While the ν(NO) for 6 is consistent with FeNO reduction, the ν(NO) for 5 appears more indicative of ligand-based reduction. Additionally, 5 and 6 engage in HNO-like chemistry in their reactions with ferric porphyrins [Fe(III)(TPP)X] (TPP = tetraphenylporphyrin; X = Cl(-), OTf(-) (trifluoromethanesulfonate anion or CF(3)SO(3)(-))) to form [Fe(TPP)NO] in stoichiometric yield via reductive nitrosylation.

Four-Coordinate AsIII-N,S Complexes: Synthesis, Structure, Properties, and Biological Relevance

Air-stable four-coordinate As(III) complexes, [As(L4)Cl] (1) and [As(L4)I] (2), were prepared using a rearranged form of the deprotonated benzothiazoline ligand, 2-(pyridin-2-yl)-2,3-dihydrobenzo[d]thiazole. Complexes 1 and 2 have been characterized by FTIR, (1)H NMR, UV-vis, and elemental microanalysis. The solid-state structure of 2 was also solved. The unusual and rare four-coordinate geometry of 2 elucidates possible binding modes and properties of N,S-ligated As(III) that may be encountered in biology.

Photocytotoxic luminescent lanthanide complexes of DTPA–bisamide using quinoline as photosensitizer

Lanthanide complexes [Ln(DTPAAQ)(DMF)] (1–3) (Ln = Pr (1), Eu (2), Tb (3), H3DTPAAQ = N,N′′-bis(3-amidoquinolyl) diethylenetriamine-N,N′,N′′-triacetic acid, DMF = N,N-dimethylformamide) were studied for their structures, photophysical properties, DNA and protein binding, DNA photocleavage, photocytotoxicity and cellular internalization. The crystal structures of complexes [Ln(DTPAAQ)(DMF)] (1–3) display a discrete mononuclear nine-coordinate {LnN3O6} tricapped-trigonal prism (TTP) coordination geometry. The europium and terbium complexes show strong luminescence properties in the visible region having a long luminescence lifetime (τ = 0.51–0.64 ms). The conjugated 3-aminoquinoline moieties act as efficient light harvesting antennae, which upon photoexcitation transfer their energy to Eu(III) or Tb(III) for their characteristic 5D0 → 7FJ or 5D4 → 7FJ f–f transitions respectively. The complexes display efficient binding affinity to DNA (Kb = 3.4 × 104 − 9.8 × 104 M−1) and BSA (KBSA = 3.03 × 104 − 6.57 × 104 M−1). Europium and terbium complexes give enhanced luminescence upon interacting with CT-DNA suggesting possible luminescence-based sensing applications for these complexes. Complexes 1–3 show moderate cleavage of supercoiled (SC) DNA to its nicked circular (NC) form on exposure to UV-A light of 312 nm involving formation of singlet oxygen (1O2) and hydroxyl radicals (˙OH) in type-II and photoredox pathways. Eu(III) and Tb(III) complexes exhibit remarkable photocytotoxicity with human cervical cancer cell line (HeLa) (IC50 = 20.7–28.5 μM) while remaining essentially noncytotoxic up to 150 μM in the dark. Complexes are nontoxic in nature thus suitable for designing cellular imaging agents. Fluorescence microscopy data reveal primarily cytosolic localization of the Eu(III) and Tb(III) complexes in HeLa cells.

Square-antiprismatic eight-coordinate complexes of divalent first-row transition metal cations: a density functional theory exploration of the electronic-structural landscape.

Density functional theory (in the form of the PW91, BP86, OLYP, and B3LYP exchange-correlation functionals) has been used to map out the low-energy states of a series of eight-coordinate square-antiprismatic (D2d) first-row transition metal complexes, involving Mn(II), Fe(II), Co(II), Ni(II), and Cu(II), along with a pair of tetradentate N4 ligands. Of the five complexes, the Mn(II) and Fe(II) complexes have been synthesized and characterized structurally and spectroscopically, whereas the other three are as yet unknown. Each N4 ligand consists of a pair of terminal imidazole units linked by an o-phenylenediimine unit. The imidazole units are the strongest ligands in these complexes and dictate the spatial disposition of the metal three-dimensional orbitals. Thus, the dx(2)-y(2) orbital, whose lobes point directly at the coordinating imidazole nitrogens, has the highest orbital energy among the five d orbitals, whereas the dxy orbital has the lowest orbital energy. In general, the following orbital ordering (in order of increasing orbital energy) was found to be operative: dxy < dxz = dyz ≤ dz(2) < dx(2)-y(2). The square-antiprism geometry does not lead to large energy gaps between the d orbitals, which leads to an S = 2 ground state for the Fe(II) complex. Nevertheless, the dxy orbital has significantly lower energy relative to that of the dxz and dyz orbitals. Accordingly, the ground state of the Fe(II) complex corresponds unambiguously to a dxy(2)dxz(1)dyz(1)dz(2)(1)dx(2)-y(2)(1) electronic configuration. Unsurprisingly, the Mn(II) complex has an S = 5/2 ground state and no low-energy d-d excited states within 1.0 eV of the ground state. The Co(II) complex, on the other hand, has both a low-lying S = 1/2 state and multiple low-energy S = 3/2 states. Very long metal-nitrogen bonds are predicted for the Ni(II) and Cu(II) complexes; these bonds may be too fragile to survive in solution or in the solid state, and the complexes may therefore not be isolable. Overall, the different exchange-correlation functionals provided a qualitatively consistent and plausible picture of the low-energy d-d excited states of the complexes.

Photosensitized samarium(III) and erbium(III) complexes of planar N,N-donor heterocyclic bases: crystal structures and evaluation of biological activity

Samarium(III) and erbium(III) complexes, namely [Sm(dpq)(DMF)2(H2O)Cl3] (1), [Sm(dppz)(DMF)2(H2O)Cl3] (2), [Er(dpq)(DMF)2Cl3] (3) and [Er(dppz)2Cl3] (4) (dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq in 1 and 3), dipyrido[3,2-a:2′,3′-c]phenazine (dppz in 2 and 4), N,N′-dimethylformamide (DMF) and water (H2O)), have been synthesized and structurally characterized. The X-ray crystal structures of complexes 1–4 show discrete mononuclear Ln(III)-based structures. Sm(III) in [Sm(dpq)(DMF)2(H2O)Cl3] (1) and [Sm(dppz)(DMF)2(H2O)Cl3] (2) adopts an eight-coordinated distorted square antiprism structure with a bidentate N,N-donor dpq/dppz ligand, three Cl− anions, two DMF molecules and one water molecule. The Er(III) complexes, [Er(dpq)(DMF)2Cl3] (3) and [Er(dppz)2Cl3] (4), show a seven-coordinated monocapped octahedral structure where Er(III) is coordinated to a bidentate dpq/dppz ligand, two DMF molecules and three Cl− anions. The crystal lattices of the complexes show intermolecular π–π stacking interactions between the planar dpq and dppz ligands. Considering the planarity and photosensitizing ability of the coordinated dpq and dppz ligands, the complexes were studied for their binding interaction with DNA and proteins and their photo-induced DNA cleavage activity. They display significant binding propensity to CT-DNA (Kb ∼ 104 M−1) in the order: 2, 4 (dppz) > 1, 3 (dpq). Complexes 1–4 bind DNA through groove binding and partial intercalation. All the complexes also show binding propensity (KBSA ∼ 105 M−1) to bovine serum albumin (BSA) protein. Complexes 1–4 efficiently cleave supercoiled (SC) ds-DNA to its nicked circular (NC) form upon exposure to UV-A light of 365 nm via formation of singlet oxygen (1O2) and a hydroxyl radical (HO˙) as reactive oxygen species in a photoredox pathway.

Overview and new insights into the thiol reactivity of coordinated NO in {MNO}(6/7/8) (M = Fe, Co) complexes.

The reactivity of free NO (NO(+), NO(•), and NO(-)) with thiols (RSH) is relatively well understood, and the oxidation state of the NO moiety generally determines the outcome of the reaction. However, NO/RSH interactions are often mediated at metal centers, and the fate of these species when bound to a first-row transition metal (e.g., Fe, Co) deserves further investigation. Some metal-bound NO moieties (particularly NO(+), yielding S-nitrosothiols) have been more thoroughly studied, yet the fate of these species remains highly condition-dependent and, for M-NO(-), an unexplored field. Herein, we present an overview of thiol reactions with metal nitrosyls that result in N-O bond activation, ligand substitution on {MNO} fragments, and/or redox chemistry. We also present our results pertaining to the thiol reactivity of nonheme {FeNO}(7/8) complexes [Fe(LN4(pr))(NO)](-/0) (1 and 2) and the noncorrin {CoNO}(8) complex [Co(LN4(pr))(NO)] (3), an isoelectronic analogue of the {FeNO}(8) complex 1. Among other products, the reaction of 1 with p-ClPhSH affords [Fe2(μ-SPh-p-Cl)2(NO)4](-) (anion of 6), a reduced Roussins red ester (rRRE), which was characterized by Fourier transform infrared (FTIR), UV-vis, electron paramagnetic resonance (EPR), and X-ray diffraction. Similarly, the reaction of 1 with glutathione in buffer affords the corresponding rRRE, which has also been spectroscopically characterized by EPR and UV-vis. The oxidation states of the metals and nitrosyls both contribute to the complex nature of these interactions, and as such, we discuss the varying product distribution accordingly. These studies shed insight into the products that may form through MNO/RSH interactions that lead to NOx activation and {MNO} redox.

Biological perspectives of a FRET based pH-probe exhibiting molecular logic gate operation with altering pH

Monitoring intracellular pH is a powerful tool towards understanding a variety of cellular functions and the prognosis of many diseases. In this study, an efficient multi-functionalized acidic pH sensitive probe 1, based on fluorescence resonance energy transfer (FRET) was prepared via the coupling of rhodamine B as a FRET acceptor and a naphthalimide fluorophore as a FRET donor using 1,4-diaminobutane as a nonconjugated linker. Morpholine was appended as a potential lysosome targeting group to the naphthalimide moiety. The probe features selective green to red switching in emission within the neutral to acidic pH range (pH 7.0 to pH 4.0), whereas it remains apparently unaffected in a basic medium with an observed pKa of ∼4.80. Moreover, probe 1 could be used to construct an INHIBIT logic gate and the corresponding complementary logic circuit by applying H+ and OH− ions as inputs based on the absorption and emission spectral changes, respectively. The probe showed efficient binding propensity to CT-DNA (Kb = 1.34 × 105 M−1) suggesting partial intercalation through planar moieties between the DNA base pairs. It also showed strong binding affinity for bovine serum albumin (BSA) protein (KBSA = 1.74 × 106 M−1) with efficient quenching of tryptophan fluorescence (97%) at λem = 345 nm. Interestingly, the naphthalimide fluorophore being an efficient photosensitizer enables the probe to show efficient DNA photocleavage under UV-A light (λ = 312 nm) with 65% conversion of supercoiled (SC) DNA to its nicked circular (NC) DNA form via the photo-generation of reactive oxygen species (ROS) at micromolar concentration under physiological conditions.