Visible light-induced cytotoxicity of a dinuclear iron(III) complex of curcumin with low-micromolar IC50 value in cancer cells

Photoactive metal complexes have emerged as potential candidates in the photodynamic therapy (PDT) of cancer. We present here the synthesis, characterization and visible light-triggered anticancer activity of two novel mixed-ligand oxo-bridged iron(III) complexes, viz., {Fe(L)(acac)}(2)(mu-O)](ClO4)(2) (1) and {Fe (L)(cur)}(2)(mu-O)](ClO4)(2) (2) where L is bis-(2-pyridylmethyl)-benzylamine, acac is acetylacetonate and cur is the monoanion of curcumin (bis(4-hydroxy-3-methoxyphenyl)-1,6-diene-3,5-dione). The crystal structure of complex 1 (as PF6 salt, 1a) shows distorted octahedral geometry of each iron(III) centre formed by the FeN3O3 core. The 1: 2 electrolytic complexes are stable in solution and retain their oxo-bridged identity in aqueous medium. Complex 2 has a strong absorption band in the visible region and shows promising photocytotoxicity in HeLa and MCF-7 cancer cells in visible light giving respective IC50 values of 3.1 +/- 0.4 lM and 4.9 +/- 0.5 lM while remains non-toxic in the dark (IC50 > 50 lM). The control complex 1 is inactive both in the light and dark. Complex 2 accumulates in cytoplasm of HeLa and MCF-7 cells as evidenced from fluorescence microscopy and triggers apoptotic cell death via light-assisted generation of reactive oxygen species (ROS). Taken together, complex 2 with its promising photocytotoxicity but negligible dark toxicity in cancer cells has significant photochemotherapeutic potential for applications in PDT. (C) 2015 Elsevier B.V. All rights reserved.

Iron(III) salicylates of dipicolylamine bases showing photo-induced anticancer activity and cytosolic localization

An iron(III) salicylate having a dipicolylamine base (andpa) with a photoactive anthracenyl moiety is prepared, characterized, and studied for its photo-induced anticancer activity and cellular localization in HeLa and MCF-7 cells. Its phenyl analogue is structurally characterized by X-ray crystallography. The complex has a ternary structure in which the dipicolylamine ligand and salicylic acid in dianionic form (sal) display respective tridentate and bidentate mode of coordination in Fe(sal)(phdpa)Cl] (1). Complex Fe(sal)(andpa)Cl] (2) having a pendant anthracenyl moiety shows significant photocytotoxicity in visible light (400-700 nm) giving IC50 values of 8.6 +/- 0.7 and 3.4 +/- 0.9 mu M in HeLa and MCF-7 cells, while being essentially nontoxic in the dark (IC50 > 100 mu M). The complex shows cytosolic localization in the cancer cells. Formation of hydroxyl radicals ((OH)-O-center dot) as the reactive oxygen species is evidenced from the pUC19 DNA photocleavage studies. (C) 2015 Elsevier Ltd. All rights reserved.

Mitochondrial selectivity and remarkable photocytotoxicity of a ferrocenyl neodymium(III) complex of terpyridine and curcumin in cancer cells

A series of four novel neodymium(III) complexes of the formulation Nd(R-tpy)(O-O)(NO3)(2)] (1-4), where R-tpy is 4'-phenyl-2,2': 6', 2''-terpyridine (Ph-tpy; 1, 2) and 4'-ferrocenyl-2,2': 6', 2''-terpyridine (Fc-tpy; 3, 4); O-O is the conjugate base of acetylacetone (Hacac; 1, 3) or curcumin (Hcurc; 2, 4), are synthesized and characterized. The single crystal structure of 1 shows that the complex is a discrete mononuclear species with the Nd(III) centre in a nine coordinate environment provided by a set of O6N3 donor atoms. Complexes 1 and 3 having the simple acac ligand are prepared as control compounds. Complex 4, possessing an appended ferrocenyl (Fc) and the curcumin moiety, is remarkably photocytotoxic to HeLa and MCF-7 cancer cells in visible light giving respective IC50 values of 0.7 mu M and 2.1 mu M while being significantly less toxic to MCF-10A normal cells (IC50 = 34 mu M) and in the dark (IC50 > 50 mu M). The phenyl appended complex 2, lacking a ferrocenyl moiety, is significantly less toxic to both the cell lines when compared with 4. Complexes 1 and 3, lacking the photoactive curcumin moiety, do not show any apparent toxicity both in light and in the dark. The cell death is apoptotic in nature and is mediated by the light-induced formation of reactive oxygen species (ROS). Fluorescence imaging experiment with HeLa cells reveals mitochondrial accumulation of complex 4 within 4 h of incubation. The complexes bind to calf thymus (ct) DNA with moderate affinity giving K-b values in the range of 10(4)-10(5) M-1. The curcumin complexes 2 and 4 cleave plasmid supercoiled DNA to its nicked circular form in visible light via O-1(2) and (OH)-O-center dot pathways. The presence of the ferrocenyl moiety is likely to be responsible for the enhanced cellular uptake and photocytotoxicity of complex 4. Thus, the mitochondria targeting complex 4, being remarkably cytotoxic in light but non-toxic in the dark and to normal cells, is a potential candidate for photochemotherapeutic applications.

I. Spectroscopic observation of discrete sites in simple liquids. II. Infrared intensity perturbations of hydrogen halide fundamentals in liquid xenon. III. Rotation of HCl in solid rare gases.

Part I

The spectrum of dissolved mercury atoms in simple liquids has been shown to be capable of revealing information concerning local structures in these liquids.

Part II

Infrared intensity perturbations in simple solutions have been shown to involve more detailed interaction than just dielectric polarization. No correlation has been found between frequency shifts and intensity enhancements.

Part III

Evidence for perturbed rotation of HCl in rare gas matrices has been found. The magnitude of the barrier to rotation is concluded to be of order of 30 cm^(-1).

I. The crystal structure of potassium bis(tricyanovinyl)amine. II. Nuclear magnetic resonance studies of alkali halide solutions. III. Elucidation of the intramolecular hydrogen bond in acetylacetone by the deuterium isotope effect on the chemical shift of the bridge hydrogen

Part I

Potassium bis-(tricyanovinyl) amine, K⁺N[C(CN)=C(CN)₂]₂^-, crystallizes in the monoclinic system with the space group Cc and lattice constants, a = 13.346 ± 0.003 Å, c = 8.992 ± 0.003 Å, B = 114.42 ± 0.02°, and Z = 4. Three dimensional intensity data were collected by layers perpendicular to b* and c* axes. The crystal structure was refined by the least squares method with anisotropic temperature factor to an R value of 0.064.

The average carbon-carbon and carbon-nitrogen bond distances in –C-CΞN are 1.441 ± 0.016 Å and 1.146 ± 0.014 Å respectively. The bis-(tricyanovinyl) amine anion is approximately planar. The coordination number of the potassium ion is eight with bond distances from 2.890 Å to 3.408 Å. The bond angle C-N-C of the amine nitrogen is 132.4 ± 1.9°. Among six cyano groups in the molecule, two of them are bent by what appear to be significant amounts (5.0° and 7.2°). The remaining four are linear within the experimental error. The bending can probably be explained by molecular packing forces in the crystals.

Part II

The nuclear magnetic resonance of ⁸¹Br and ¹²⁷I in aqueous solutions were studied. The cation-halide ion interactions were studied by studying the effect of the Li⁺, Na⁺, K⁺, Mg⁺⁺, Cs⁺ upon the line width of the halide ions. The solvent-halide ion interactions were studied by studying the effects of methanol, acetonitrile, and acetone upon the line width of ⁸¹Br and ¹²⁷I in the aqueous solutions. It was found that the viscosity plays a very important role upon the halide ions line width. There is no specific cation-halide ion interaction for those ions such as Mg⁺⁺, Di⁺, Na⁺, and K⁺, whereas the Cs⁺ - halide ion interaction is strong. The effect of organic solvents upon the halide ion line width in aqueous solutions is in the order acetone ˃ acetonitrile ˃ methanol. It is suggested that halide ions do form some stable complex with the solvent molecules and the reason Cs⁺ can replace one of the ligands in the solvent-halide ion complex.

Part III

An unusually large isotope effect on the bridge hydrogen chemical shift of the enol form of pentanedione-2, 4(acetylacetone) and 3-methylpentanedione-2, 4 has been observed. An attempt has been made to interpret this effect. It is suggested from the deuterium isotope effect studies, temperature dependence of the bridge hydrogen chemical shift studies, IR studies in the OH, OD, and C=O stretch regions, and the HMO calculations, that there may probably be two structures for the enol form of acetylacetone. The difference between these two structures arises mainly from the electronic structure of the π-system. The relative population of these two structures at various temperatures for normal acetylacetone and at room temperature for the deuterated acetylacetone were calculated.

I. Fundamental limitations in microelectronics. II. Power Schottky diode design and comparison with the junction diode. III. Permittivity of strontium titanate

Part I

The physical phenomena which will ultimately limit the packing density of planar bipolar and MOS integrated circuits are examined. The maximum packing density is obtained by minimizing the supply voltage and the size of the devices. The minimum size of a bipolar transistor is determined by junction breakdown, punch-through and doping fluctuations. The minimum size of a MOS transistor is determined by gate oxide breakdown and drain-source punch-through. The packing density of fully active bipolar or static non-complementary MOS circuits becomes limited by power dissipation. The packing density of circuits which are not fully active such as read-only memories, becomes limited by the area occupied by the devices, and the frequency is limited by the circuit time constants and by metal migration. The packing density of fully active dynamic or complementary MOS circuits is limited by the area occupied by the devices, and the frequency is limited by power dissipation and metal migration. It is concluded that read-only memories will reach approximately the same performance and packing density with MOS and bipolar technologies, while fully active circuits will reach the highest levels of integration with dynamic MOS or complementary MOS technologies.

Part II

Because the Schottky diode is a one-carrier device, it has both advantages and disadvantages with respect to the junction diode which is a two-carrier device. The advantage is that there are practically no excess minority carriers which must be swept out before the diode blocks current in the reverse direction, i.e. a much faster recovery time. The disadvantage of the Schottky diode is that for a high voltage device it is not possible to use conductivity modulation as in the p i n diode; since charge carriers are of one sign, no charge cancellation can occur and current becomes space charge limited. The Schottky diode design is developed in Section 2 and the characteristics of an optimally designed silicon Schottky diode are summarized in Fig. 9. Design criteria and quantitative comparison of junction and Schottky diodes is given in Table 1 and Fig. 10. Although somewhat approximate, the treatment allows a systematic quantitative comparison of the devices for any given application.

Part III

We interpret measurements of permittivity of perovskite strontium titanate as a function of orientation, temperature, electric field and frequency performed by Dr. Richard Neville. The free energy of the crystal is calculated as a function of polarization. The Curie-Weiss law and the LST relation are verified. A generalized LST relation is used to calculate the permittivity of strontium titanate from zero to optic frequencies. Two active optic modes are important. The lower frequency mode is attributed mainly to motion of the strontium ions with respect to the rest of the lattice, while the higher frequency active mode is attributed to motion of the titanium ions with respect to the oxygen lattice. An anomalous resonance which multi-domain strontium titanate crystals exhibit below 65°K is described and a plausible mechanism which explains the phenomenon is presented.

Studies on the solution structures of lanthanide(III) complexes of DTPA-BIN by NMR

The solution structures of diamagnetic lanthanide (III) complexes of DTPA-BIN (Ln = La, Y, Lu, Sc) have been investigated by H-1 NMR, C-13 NMR and 2D NMR. For each complex, two or more species of asymmetric conformations with little distinction were identified at room temperature. And their solution structures vary with the radius of the central metals. NMR spectra support the hypothesis that Sc3+ with smaller radius formed an eight-coordinated structure with DTPA-BIN, La3+ with larger radius formed nine- or ten-coordinated structures with DTPA-BIN, and Y (DTPA-BIN) and Lu (DTPA-BIN) had nine-coordinated solution structures. The solution structure of Gd (DTPA-BIN) was obtained from the similarity of radius between Gd3+ and Y3+, which is a nine-coordinated structure formed by three nitrogens, three acetate oxygens, two acetyl oxygens, one water molecule and a gadolinium(III) cation.

Water exchange rates of water-soluble manganese(III) porphyrins of therapeutical potential.

The activation parameters and the rate constants of the water-exchange reactions of Mn(III)TE-2-PyP(5+) (meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin) as cationic, Mn(III)TnHex-2-PyP(5+) (meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin) as sterically shielded cationic, and Mn(III)TSPP(3-) (meso-tetrakis(4-sulfonatophenyl)porphyrin) as anionic manganese(iii) porphyrins were determined from the temperature dependence of (17)O NMR relaxation rates. The rate constants at 298 K were obtained as 4.12 x 10(6) s(-1), 5.73 x 10(6) s(-1), and 2.74 x 10(7) s(-1), respectively. On the basis of the determined entropies of activation, an interchange-dissociative mechanism (I(d)) was proposed for the cationic complexes (DeltaS(double dagger) = approximately 0 J mol(-1) K(-1)) whereas a limiting dissociative mechanism (D) was proposed for Mn(III)TSPP(3-) complex (DeltaS(double dagger) = +79 J mol(-1) K(-1)). The obtained water exchange rate of Mn(III)TSPP(3-) corresponded well to the previously assumed value used by Koenig et al. (S. H. Koenig, R. D. Brown and M. Spiller, Magn. Reson. Med., 1987, 4, 52-260) to simulate the (1)H NMRD curves, therefore the measured value supports the theory developed for explaining the anomalous relaxivity of Mn(III)TSPP(3-) complex. A magnitude of the obtained water-exchange rate constants further confirms the suggested inner sphere electron transfer mechanism for the reactions of the two positively charged Mn(iii) porphyrins with the various biologically important oxygen and nitrogen reactive species. Due to the high biological and clinical relevance of the reactions that occur at the metal site of the studied Mn(iii) porphyrins, the determination of water exchange rates advanced our insight into their efficacy and mechanism of action, and in turn should impact their further development for both diagnostic (imaging) and therapeutic purposes.