J. Appl. Cryst.の発刊に際して

Comparison of acidic and alkaline catalysts for preparation of fatty acid methyl esters from ovine muscle with emphasis on conjugated linoleic acid.

Although copper-ligand complexes appear to be promising as a new class of therapeutics, other than the family of copper(ii) coordination compounds referred to as casiopeinas these compounds have yet to reach the clinic for human use. The pharmaceutical challenges associated with developing copper-based therapeutics will be presented in this article along with a discussion of the potential for high-throughput chemistry, computer-aided drug design, and nanotechnology to address the development of this important class of drug candidates.

A Perspective – can copper complexes be developed as a novel class of therapeutics?

Metal complexes with organelle specificity and potent but selective cytotoxicity are highly desirable. In this work, we report the synthesis, characterization and cytotoxicity of six novel copper(II) complexes of the formula Cu(R-tpy)(N-O)]NO3 (1-6), where R-tpy is 4'-phenyl-2,2': 6', 2 `'-terpyridine (Ph-tpy; 1-3) or 4'-ferrocenyl-2,2': 6', 2 `'-terpyridine (Fc-tpy; 4-6), N-O is the anion of 8-hydroxyquinoline (HQ in 1, 4), 5-chloro-7-iodo-8-hydroxyquinoline (CQ in 2, 5) or 5-nitro-8-hydroxyquinoline (NQ in 3, 6). The complex Cu(Fc-tpy)(2)](ClO4)(2) (7) has also been prepared as a control and structurally characterized. The optimized geometries and the frontier orbitals of the complexes have been obtained from DFT calculations. The ferrocenyl appended complexes having the anticancer active CQ (in 5) and NQ (in 6) ligands show remarkable cytotoxicity, giving the respective IC50 values of 0.75 mu M and 0.52 mu M in HeLa and 1.3 mu M and 2.6 mu M in MCF-7 cancer cells. The phenyl appended complexes 2 and 3 are less active than their ferrocenyl analogues in both the cells while the complexes of HQ (in 1, 4) are the least active. Interestingly, complexes 4-6 are significantly less toxic to MCF-10A normal cells. The DCFDA, annexin-V-FITC and propidium iodide nuclear staining assays reveal an apoptotic mechanism of cell death which is attributable to the metal-assisted generation of reactive oxygen species. Imaging experiments on HeLa cells reveals that complex 5 accumulates primarily inside the mitochondria. The complexes bind to calf thymus DNA with moderate affinity giving K-b values in the range of 6.3 x 10(4)-7.4 x 10(4) M-1 and to HSA protein with significant affinity giving KHSA values in the range of 8.6 x 10(4)-1.3 x 10(5) M-1. Their affinity for DNA suggests that mitochondrial DNA could be the target while their affinity for HSA suggests that they could be transported by HSA in the blood. This work is the first report to show that the ferrocenyl appended copper(II) complexes of hydroxyquinoline ligands are remarkably cytotoxic to cancer cells but significantly less toxic to normal cells.

Novel mitochondria targeted copper(II) complexes of ferrocenyl terpyridine and anticancer active 8-hydroxyquinolines showing remarkable cytotoxicity, DNA and protein binding affinity

The zinc oxide (ZnO) nanoparticles were successfully synthesized by using aqueous extracts of Aloe vera gel/leaf and Hibiscus sabdariffa leaf, and characterized by FT IR, UV-Vis, XRD, SEM, and EDX techniques. For comparison purposes, ZnO nanoparticles was also synthesized by chemical method. Phytochemical screening of the A. vera gel and leaf and H. sabdariffa leaf extracts showed the presence of alkaloids, carbohydrates, flavonoids, gums and mucilages, saponins, phenolic compounds, tannins, and terpenoids. FT IR spectra showed the presence of functional groups and protein as the stabilizing agent surrounding the ZnO nanoparticles. UV-Vis spectra of ZnO nanoparticles exhibit the characteristic absorption band in the range of 344–360 nm, which can be assigned to the intrinsic bandgap absorption of ZnO due to the electron transitions from the valence band to the conduction band. Powder XRD patterns confirmed the hexagonal wurtzite structure. Further, the SEM analysis also indicates the hexagonal rod shape structure of the ZnO nanoparticles. EDX spectra confirmed the chemical composition of the ZnO nanoparticles synthesized by both biological and chemical methods. In vitro antibacterial activity of ZnO nanoparticles synthesized by both biological and chemical methods were performed on three Gram (−ve) (Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa) and one Gram (+ve) (Staphylococcus aureus) bacteria, in which the ZnO nanoparticles obtained by biological method showed excellent bactericidal activity over that obtained by chemical method. All the ZnO nanoparticles showed promising antioxidant activity determined by five different methods such as 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS); 2,2′-diphenyl-1-picrylhydrazyl (DPPH); hydrogen peroxide (H2O2); superoxide radical scavenging; and hydroxyl radical scavenging assays. In vitro cytotoxicity of the ZnO nanoparticles were tested against three cancerous cell lines such as human breast adenocarcinoma (MCF-7), cervical (HeLa) and epithelioma (Hep-2), and one normal human dermal fibroblasts (NHDF) cell lines by MTT assay. Apoptosis induction was further confirmed by flow cytometry and cell cycle arrest. The ZnO nanoparticles obtained by biological method display remarkable cytotoxicity against the MCF-7 cell line, and found to be more potent than the widely used drug cisplatin.

Biosynthesis of zinc oxide nanoparticles using plant extracts of Aloe vera and Hibiscus sabdariffa: Phytochemical, antibacterial, antioxidant and anti-proliferative studies

A series of homoleptic bis(terpyridine)copper(II) complexes of the type [Cu(L1–5)2]Cl2 (1–5), where L1–5 = 4′-(4-substituted)-2,2′:6′,2′′-terpyridines, have been synthesized and characterized. The molecular structure of complex 2 was confirmed by the single crystal XRD technique, and the geometry of the complexes is best described as distorted octahedral. Structural parameters from the crystallographic and DFT studies are in good agreement with each other. The small HOMO–LUMO energy gap supports bioefficacy of the complexes. DNA binding studies show high intrinsic binding constant values 1.53 ± 0.15, 1.62 ± 0.08 and 3.09 ± 0.12 × 105 M−1 for complexes 1, 2 and 3, respectively, with intercalative mode of binding to CT-DNA. The binding results were further supported by molecular docking studies. The experimental results indicate that the interaction between the complexes and BSA protein involves a static quenching mechanism. The molecular docking studies with c-Met tyrosine kinase receptors show hydrophobic and π–π interactions. All the complexes bring about hydroxyl radical mediated DNA cleavage in the presence of H2O2. In vitro cytotoxicities of the complexes (1–3) were tested against three cancerous cell lines, namely human breast adenocarcinoma (MCF-7), epithelioma (Hep-2) and cervical (HeLa) cell lines, and one non-tumorigenic human dermal fibroblast (NHDF) cell line by MTT reduction assay. The morphological assessment data obtained using Hoechst 33258 staining revealed that complex 3 induces apoptosis much more effectively than the other complexes.

Targeting of DNA molecules, BSA/c-Met tyrosine kinase receptors and anti-proliferative activity of bis(terpyridine)copper(II) complexes

A novel organic nonlinear optical (NLO) crystal, isonicotinamidium picrate (ISPA) was synthesized and grown by the slow evaporation method Formation of the new crystalline compound was confirmed by a single crystal X-ray diffraction study The title compound crystallizes in the monoclinic crystal system with the space group of P21/n DFT was carried out to calculate the bond lengths and bond angles Structural parameters obtained from single crystal XRD and DFT studies are in good agreement with each other The frontier energy gaps calculated theoretically are useful to understand the charge transfer taking place in the molecule Polarizability of the ISPA compound is found using Penn gap analysis and the Clausius–Mossotti equation The UV-vis-NIR spectral study showed that the grown crystal is transparent in the entire visible region with the lower cut-off wavelength of 469 nm The four independent tensor coefficients of dielectric permittivity were found to be e11 = 142, e22 = 462, e33 = 623 and e13 = 556 from the dielectric measurements The titular compound ISPA is thermally stable up to 229 °C assessed by thermogravimetric and differential thermal (TG-DTA) analyses The specific heat capacity of ISPA is found to be 349 J g−1 K−1 The laser induced surface damage threshold of the grown crystal was measured to be 022537 GW cm−2 for 1064 nm Nd:YAG laser radiation Nonlinear refractive index (n2), absorption coefficient (β) and third order nonlinear susceptibility (χ(3)) were determined using the Z-scan technique The optical limiting study revealed that the transmitted output power increases linearly with the input power up to the irradiance of around 325 mW mm−2

A new organic NLO material isonicotinamidium picrate (ISPA): crystal structure, structural modeling and its physico-chemical properties

An organic nonlinear optical (NLO) crystal, imidazolium diphenylacetate diphenylacetic acid (IDA), was synthesized and grown by the slow evaporation method. Formation of the new crystalline compound was confirmed by single crystal X-ray diffraction study. The title compound crystallizes in the triclinic crystal system with the space group P. UV-vis-NIR spectral study showed that the grown crystal is transparent in the entire visible region with a lower cut-off wavelength of 275 nm. Density functional theory (DFT) calculations were carried out to calculate the frontier molecular orbitals and natural bonding orbitals of the IDA compound. The frontier energy gaps calculated theoretically were useful to understand the charge transfer taking place in the molecule. The natural bonding orbital analysis provides a convenient basis for the investigation of the charge transfer or conjugative interactions in the molecular system. Vicker's microhardness study revealed that the title material belongs to the soft material category. The values of fracture toughness, brittleness index and yield strength have also been calculated for Palmqvist and median types of cracks. The title compound IDA is thermally stable up to 201 °C, as assessed by thermogravimetric and differential thermal (TG-DTA) analyses. The specific heat capacity of IDA is found to be 3.25 J kg−1 K−1 at 65 °C. The laser induced surface damage threshold of the grown crystal was measured to be 0.2645 GW cm−2 with 1064 nm Nd:YAG laser radiation. The nonlinear refractive index (n2), absorption coefficient (β) and third order nonlinear susceptibility (χ(3)) were determined using the Z-scan technique. An optical limiting study revealed that the transmitted output power increases linearly with the input power up to an irradiance of around 3.6 mW cm−2.

Crystal structure, molecular packing, FMO, NBO, nonlinear optical and optical limiting properties of an organic imidazolium diphenylacetate diphenylacetic acid single crystal

Gas‐liquid chromatography of d‐biotin

A series of six new bis(thiosemicarbazone)copper(I) complexes of the type [Cu(L1–6)2Cl] (1−6) were synthesized and characterized. The complexes adopted trigonal planar ′Y′ shaped geometry coordinating through two thione sulphur atoms of two ligand molecules and one chloride ion. All the complexes intercalatively bind with calf thymus DNA (CT−DNA) as evidenced by spectral and molecular docking studies. The absorption and emission spectral techniques confirmed the strong interaction of the complexes with BSA via static quenching mode. The complexes efficiently cleave pBR322 DNA via hydrolytic pathway, and significantly interact with epidermal growth factor receptor. All the complexes were assessed for their anti‐proliferative activity, in which the complexes 2, 3 and 4 containing methyl, methoxy and hydroxyl groups, respectively, showed significant activity. The complexes induce apoptosis in EAC cells as evidenced by acridine orange (AO)/ethidium bromide (EB), Hoechst 33258 and propidium iodide (PI) staining methods, and cell cycle analysis. Cellular uptake studies revealed the ability of the complexes to go into the cytoplasm and accumulation in the cell nuclei. The complexes are involved in the generation of reactive oxygen species (ROS), mitochondrial mediated and caspase‐dependent apoptosis. Further, using a female Swiss albino mice model, we found that the complexes 2 and 3 inhibited Ehrlich ascites carcinoma (EAC) tumour cell growth in vivo.

Bis(thiosemicarbazone)copper(I) Complexes as Prospective Therapeutic Agents: Interaction with DNA/BSA Molecules, and In Vitro and In Vivo Anti-Proliferative Activities

Vijayan Viswanathan

Papers

Targeting of DNA molecules, BSA/c-Met tyrosine kinase receptors and anti-proliferative activity of bis(terpyridine)copper(II) complexes

A new organic NLO material isonicotinamidium picrate (ISPA): crystal structure, structural modeling and its physico-chemical properties

Crystal structure, molecular packing, FMO, NBO, nonlinear optical and optical limiting properties of an organic imidazolium diphenylacetate diphenylacetic acid single crystal

Gas‐liquid chromatography of d‐biotin

Bis(thiosemicarbazone)copper(I) Complexes as Prospective Therapeutic Agents: Interaction with DNA/BSA Molecules, and In Vitro and In Vivo Anti-Proliferative Activities