Anticancer, antimicrobial and photocatalytic activities of a new pyrazole containing thiosemicarbazone ligand and its Co(III) and Ni(II) complexes: Synthesis, spectroscopic characterization and X-ray crystallography.

A new pyrazole based thiosemicarbazone ligand, 5-methyl-3-formylpyrazole-N(4)-isopropylthiosemicarbazone, (HMPzNHPri) (compound I), and its cobalt(III) and nickel(II) complexes, [Co(MPzNHPri)2]Cl (compound II) and [Ni(HMPzNHPri)2]Br2 (compound III), respectively, have been synthesized and characterized through various physico-chemical and spectroscopic studies. Both the reported Co(III) and Ni(II) complexes are cationic in nature and behave as 1:1 and 1:2 electrolytes in MeOH, respectively. Electronic spectral features of the complexes have classified them as distorted octahedral ones. IR spectral data (4000-450 cm-1) have suggested a monoprotic tridentate (NNS) function of compound I coordinating to the Co(III) ion via the pyrazolyl (tertiary) ring nitrogen, azomethine nitrogen and thiolato sulphur atom; while for compound III, compound I has been found to act as neutral NNS tridentate one, coordinating to Ni(II) via the pyrazolyl iminic nitrogen, azomethine nitrogen and thioketo sulphur. Structural features of all the compounds are confirmed by the single crystal X-ray data. All the compounds reported here have been found to exhibit significant photocatalytic activity towards degradation of Methylene Blue (MB) under UV radiation. Anticancer activity of all the three compounds against cancer cell lines (HeLa and A549) and a normal cell line (HEK293) have been investigated. Compound II has been found to be more efficient against the human cervical cancer cell (HeLa) and the lung cancer cell (A549) than compounds I and III. The ligand and both the complexes display potential activities against both gram-positive (Bacillus subtilis MTCC 7193) and gram-negative bacteria (E. coli MTCC 1610).

Alkyl backbone variations in common ß-diketiminate ligands and applications to N-heterocyclic silylene chemistry.

We report the extension of the common ß-diketimine proligand class, RArnacnacH (HC(RCNAr)2H), where R is an alkyl group such as Et or iPr, plus Ph, and Ar is a sterically demanding aryl substituent such as Dip = 2,6-diispropylphenyl, Dep = 2,6-diethylphenyl, Mes = 2,4,6-trimethylphenyl or mesityl, Xyl = 2,6-dimethylphenyl, via one-pot condensation procedures. When a condensation reaction is carried out using the chemical dehydrating agent PPSE (polyphosphoric acid trimethylsilylester), ß-diketiminate phosphorus(V) products such as (iPrMesnacnac)PO2 can also be obtained, which can be converted to the respective proligand iPrMesnacnacH via alkaline hydrolysis. The RArnacnacH proligands can be converted to their alkali metal complexes with common methods and we have found that deprotonation of iPrDipnacnacH is significantly more sluggish than that of related ß-diketimines with smaller backbone alkyl groups. The basicity of the RArnacnac- anions can play a role in the success of their salt metathesis chemistry and we have prepared and structurally characterised the EtDipnacnac-derived silicon(II) compounds (EtDipnacnac)SiBr and (EtDipnacnac')Si, where EtDipnacnac' is the deprotonated variant MeCHC(NDip)CHC(NDip)Et.

[3-Meth-oxy-5-(meth-oxy-carbon-yl)isoxazol-4-yl](4-meth-oxy-phen-yl)iodo-nium 2,2,2-tri-fluoro-acetate.

A new isoxazole-based iodo-noium salt, C13H13INO5 +·C2F3O2 -, has been synthesized and structurally characterized. In the crystal, ions are linked by short I⋯O contacts to form a neutral tetra-ion aggregate. These combine with C-H⋯F and C-H⋯O inter-actions to form double-layered two-dimensional sheets in the (001) plane.

Synthesis and Conformational Analysis of Fluorinated Uridine Analogues Provide Insight into a Neighbouring-Group Participation Mechanism.

Fluorinated nucleoside analogues have attracted much attention as anticancer and antiviral agents and as probes for enzymatic function. However, the lack of direct synthetic methods, especially for 2',3'-dideoxy-2',3'-difluoro nucleosides, hamper their practical utility. In order to design more efficient synthetic methods, a better understanding of the conformation and mechanism of formation of these molecules is important. Herein, we report the synthesis and conformational analysis of a 2',3'-dideoxy-2',3'-difluoro and a 2'-deoxy-2'-fluoro uridine derivative and provide an insight into the reaction mechanism. We suggest that the transformation most likely diverges from the SN1 or SN2 pathway, but instead operates via a neighbouring-group participation mechanism.

Site-Specific Iron Substitution in STA-28, a Large Pore Aluminophosphate Zeotype Prepared by Using 1,10-Phenanthrolines as Framework-Bound Templates.

An AlPO4 zeotype has been prepared using the aromatic diamine 1,10-phenanthroline and some of its methylated analogues as templates. In each case the two template N atoms bind to a specific framework Al site to expand its coordination to the unusual octahedral AlO4 N2 environment. Furthermore, using this framework-bound template, Fe atoms can be included selectively at this site in the framework by direct synthesis, as confirmed by annular dark field scanning transmission electron microscopy and Rietveld refinement. Calcination removes the organic molecules to give large pore framework solids, with BET surface areas up to 540 m2 g-1 and two perpendicular sets of channels that intersect to give pore space connected by 12-ring openings along all crystallographic directions.

A Luminescent Amine-Functionalized Metal-Organic Framework Conjugated with Folic Acid as a Targeted Biocompatible pH-Responsive Nanocarrier for Apoptosis Induction in Breast Cancer Cells.

Folic acid amine-functionalized metal-organic framework (FOLA@NH2-Eu:TMU-62) with luminescent properties loaded with 5-fluorouracil (5-Fu), as an anticancer medication, was used to construct a new cancer targeted drug delivery system in the present study. The 5-Fu release from this targeted carrier along with MTT assay and trypan blue dye exclusion test results also exhibited pH-controlled characteristics of the given carrier in acidic environments, which is very suitable for targeting solid tumors. Then, the inhibitory action of 5-Fu-loaded FOLA@NH2-Eu:TMU-62 for Michigan Cancer Foundation-7 (MCF7) cell migration was explored according to scratch wound healing assays. Based on the results, the FOLA@NH2-Eu:TMU-62 carrier was not toxic for MCF-10A normal cells, but it was significantly toxic for MCF-7 breast cancer ones, revealing that the FOLA@NH2-Eu:TMU-62 carrier could be utilized in accurate cancer treatments through apoptotic pathways with higher reactive oxygen species compared with 5-Fu alone. This cancer-targeted design of FOLA@NH2-Eu:TMU-62 could thus pave the way for synergistic effects of targeting as well as organized release capabilities.

Chiral AuI - and AuIII -Isothiourea Complexes: Synthesis, Characterization and Application.

During an investigation into the potential union of Lewis basic isothiourea organocatalysis and gold catalysis, the formation of gold-isothiourea complexes was observed. These novel gold complexes were formed in high yield and were found to be air- and moisture stable. A series of neutral and cationic chiral gold(I) and gold(III) complexes bearing enantiopure isothiourea ligands was therefore synthesized and fully characterized. The steric and electronic properties of the isothiourea ligands was assessed through calculation of their percent buried volume and the synthesis and analysis of novel iridium(I)-isothiourea carbonyl complexes. The novel gold(I)- and gold(III)-isothiourea complexes have been applied in preliminary catalytic and biological studies, and display promising preliminary levels of catalytic activity and potency towards cancerous cell lines and clinically relevant enzymes.

Chitosan Immobilization on Bio-MOF Nanostructures: A Biocompatible pH-Responsive Nanocarrier for Doxorubicin Release on MCF-7 Cell Lines of Human Breast Cancer.

In this work, a bio-metal-organic framework (Bio-MOF) coated with a monodispersed layer of chitosan (CS; CS/Bio-MOF) was synthesized and applied as a pH-responsive and target-selective system for delivery of doxorubicin (DOX) in the treatment of breast cancer. The efficiency of the nanocarrier in loading and releasing DOX was assessed at different pH levels. To monitor the in vitro drug release behavior of the drug-loaded carrier, the carrier was immersed in a phosphate buffered saline solution (PBS, pH 7.4) at 37 °C. According to the observations, the nanocarrier presents a slow and continuous release profile as well as a noticeable drug loading capacity. In addition, the carrier demonstrates a pH-responsive and target-selective behavior by releasing a high amount of DOX at pH 6.8, which is indicative of tumor cells and inflamed tissues and releasing a substantially lower amount of DOX at higher pH values. In addition, the results indicated that pH is effective on DOX uptake by CS/Bio-MOF. A 3.6 mg amount of DOX was loaded into 10 mg of CS/Bio-MOF, resulting in a 21.7% removal at pH 7.4 and 93.0% at pH 6.8. The collapsing and swelling of the CS layers coated on the surface of the Bio-MOFs were found to be responsible for the observed pH dependence of DOX delivery. Moreover, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the trypan blue test were performed on the MCF-7 (breast cancer) cell line in the presence of the CS/Bio-MOF carrier to confirm its biological compatibility. In addition, Annexin V staining was conducted to evaluate the cytotoxicity of the free and loaded DOX molecules. On the basis of the obtained optical microscopy, MTT assay, fluorescence microscopy, and dyeing results, the CS/Bio-MOF carrier greatly enhances cellular uptake of the drug by the MCF-7 cells and, therefore, apoptosis of the cells due to its biocompatibility and pH-responsive behavior.

The effect of different parameters under ultrasound irradiation for synthesis of new nanostructured Fe3O4@bio-MOF as an efficient anti-leishmanial in vitro and in vivo conditions.

In this work, a magnetic bio-metal-organic framework (MBMOF) nanocomposite with porous-layer open morphology is synthesized through a simple sonochemical approach and its effects on Leishmania major (MRHO/IR/75/ER) under both in vitro and in vivo conditions are investigated. The effects of sonication time, initial concentration of reagents and sonication power on size and morphology of MBMOF nanocomposites have been investigated and optimized. A comparison was then made between the structural information of the nanostructures and that of the bio-metal-organic framework crystals. Using the powder X-ray diffraction (PXRD), field emission scanning electron microscope (FE-SEM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), energy dispersive analysis of X-ray (EDAX), vibrating sample magnetometer (VSM), thermogravimetric analysis (TGA), and Brunauer-Emmet-Teller (BET) techniques, the prepared MBMOF nanocomposites were characterized. The mean numbers of promastigotes (cell/ml) in different MBMOF concentrations (3.12, 6.25, 12.5, 25, 50, 100, 200 and 400 µg mL-1) were determined by direct counting after 24, 48 and 72 h. Using MTT assays, the cytotoxic impacts of the MBMOF nanocomposites on promastigotes, intracellular amastigotes, and J774 macrophages were estimated. In order to investigate their therapeutic effects, the prepared MBMOF nanocomposites (25 and 12.5 µg mL-1) were used as ointment three times a week to treat Leishmania major in BALB/c mice. The lesion size and weight of mice were assessed before and during the treatment. The parasitic loads were measured in spleen and liver through the culture. After 72 h, the INF-γ and IL-4 cytokines levels in the supernatant of the spleen culture were measured. To the best of the authors' knowledge, this study is the first to attempt to synthesize the bio-MOFs through an in-situ sonosynthesis route under ultrasound irradiation and examine their cytotoxicity effects on Leishmania major under in vitro and in vivo conditions.

Morphology- and size-controlled synthesis of a metal-organic framework under ultrasound irradiation: An efficient carrier for pH responsive release of anti-cancer drugs and their applicability for adsorption of amoxicillin from aqueous solution.

In this study, we have reported a biocompatible metal-organic framework (MOF) with ultra-high surface area, which we have shown to have uses as both a cancer treatment delivery system and for environmental applications. Using a sonochemical approach, highly flexible organic H3BTCTB and ditopic 4,4'-BPDC ligands, along with modulators of acetic acid and pyridine were combined to prepare a Zn(II)-based metal-organic framework, DUT-32, [Zn4O(BPDC)(BTCTB)4/3(DEF)39.7(H2O)11.3]. Powder X-ray diffraction (PXRD), field-emission scanning electron microscopy (FE-SEM), and Fourier transform infrared spectroscopy (FTIR) were used to characterize, the particle size, shape, and structure of the DUT-32. To show the effects of shape and size of DUT-32 micro/nano-structures on doxorubicin (DOX) drug release and amoxicillin (AMX) adsorption, time of sonication, initial reagent concentrations, irradiation frequency, and acetic acid to pyridine molar ratios were optimized. The drug-loaded DUT-32 was soaked in simulated body fluid (SBF) and the drug release ratio was monitored through release time to perform in vitro drug release test. A slow and sustained release was observed for DUT-32 micro/nano-structures, having a considerable drug loading capacity. At the pH values 7.4-4.5, various profiles of pH-responsive release were achieved. Also, the prepared DUT-32 micro/nano-structures are found to be biocompatible with PC3 (prostate cancer) and HeLa (cervical cancer) cell lines, when tested by MTT assay. Moreover, DUT-32 micro/nano-structures were studied to show AMX adsorption from aqueous solution. Finally, kinetic studies indicated that AMX adsorption and drug release of DOX via this MOF are of first-order kinetics.

Anticancer activities of a ß-amino alcohol ligand and nanoparticles of its copper(ii) and zinc(ii) complexes evaluated by experimental and theoretical methods.

2-(2-(2-Hydroxyethylamino)ethylamino)cyclohexanol (HEAC) and copper and zinc complexes, [Cu(HEAC)Cl]Cl (1), [Cu(HEAC)Br]Br (2), [Zn(HEAC)Cl2] (3), were prepared and identified by elemental analysis, FT-IR, UV-Vis, 1H NMR spectroscopy and single-crystal X-ray diffraction. Also nanoparticles of 1-3 were prepared for anticancer studies by ultrasonic irradiation. Particle size and morphology of the nano particles are investigated by PXRD and SEM, respectively. X-ray analysis revealed that the ionic complexes 1 and 2 are isostructural. In the structure of complexes 1 and 2, the metal atom has a CuN2O2X (X: Cl (1), Br (2)) environment with square-pyramidal geometry, containing the tetradentate N2O2-donor HEAC. The bond length of the axial position in the square-pyramidal geometry of 1 and 2 is elongated. Complex 3 has a ZnN2OCl2 environment with trigonal bipyramidal geometry around the zinc atom in which the HEAC acts as mer-N2O-donor. The ability of HEAC and nano particles 1-3 to interact with the nine biomacromolecules (BRAF kinase, CatB, DNA gyrase, HDAC7, rHA, RNR, TrxR, TS and Top II) are investigated by docking calculations. For examination of the docking results, the in vitro activities of four compounds against the human leukemia cell line K562 were investigated by evaluation of IC50 values and mode of cell death (apoptosis). The thermodynamic stability of the compounds along with the charge distribution pattern were studied by DFT and NBO analysis, respectively.

Total synthesis of dehaloperophoramidine using a highly diastereoselective Hosomi-Sakurai reaction.

The synthesis of dehaloperophoramidine, a non-halogenated derivative of the marine natural product perophoramidine, and its biological activity towards HCT116, HT29 and LoVo colorectal carcinoma cells is reported. A [3,3]-Claisen rearrangement and an epoxide opening/allylsilylation reaction installed the contiguous all-carbon quaternary stereocentres with the required relative stereochemistry.

General and mild Ni(0)-catalyzed α-arylation of ketones using aryl chlorides.

A general methodology for the α-arylation of ketones using a nickel catalyst has been developed. The new well-defined [Ni(IPr*)(cin)Cl] (1 c) pre-catalyst showed great efficiency for this transformation, allowing the coupling of a wide range of ketones, including acetophenone derivatives, with various functionalised aryl chlorides. This cinnamyl-based Ni-N-heterocyclic carbene (NHC) complex has demonstrated a different behaviour to previously reported NHC-Ni catalysts. Preliminary mechanistic studies suggest a Ni(0)/Ni(II) catalytic cycle to be at play.

An asymmetric pericyclic cascade approach to 3-alkyl-3-aryloxindoles: generality, applications and mechanistic investigations.

The reaction of L-serine derived N-arylnitrones with alkylarylketenes generates asymmetric 3-alkyl-3-aryloxindoles in good to excellent yields (up to 93%) and excellent enantioselectivity (up to 98% ee) via a pericyclic cascade process. The optimization, scope and applications of this transformation are reported, alongside further synthetic and computational investigations. The preparation of the enantiomer of a Roche anti-cancer agent (RO4999200) 1 (96% ee) in three steps demonstrates the potential utility of this methodology.

A modular approach for the synthesis of nanometer-sized polynitroxide multi-spin systems.

The synthesis of rigid symmetric polyradical model systems with inter-spin distances between 1.4 and 4 nm and their room temperature continuous wave (CW) EPR spectra are reported. Conditions for attachment of the spin-label via esterification have been optimized on the direct synthesis of polyradicals from commercially available polyphenols and the carboxylic acid functionalized nitroxide TPC. A common synthetic protocol utilizing 4-hydroxy-4'-iodobiphenyl as a key building block has been used to synthesize an equilateral biradical and a triradical in only two steps from commercially available starting materials. The first synthesis of a tetraradical based upon an adamantane core bearing six equivalent nitroxide-nitroxide distances is also reported. These systems are very promising candidates for studying multi-spin effects in pulsed EPR distance measurements.

Nickel-catalysed carboxylation of organoboronates.

A nickel/N-heterocyclic carbene (NHC) catalysed carboxylation of aryl-, heteroaryl- and alkenylboronates, affording the corresponding carboxylic acids, has been developed. This transformation proceeds under one atmosphere of CO2 with a broad range of substrates and exhibits good functional group compatibility.

[Pd(IPr*)(cinnamyl)Cl]: an efficient pre-catalyst for the preparation of tetra-ortho-substituted biaryls by Suzuki-Miyaura cross-coupling.

The bigger the better: The new well-defined [Pd(IPr*)(cin)Cl] pre-catalyst is described. This complex proves to be highly active in the Suzuki-Miyaura cross-coupling for the synthesis of tetra-ortho-substituted biaryls under mild conditions. IPr* is reported as the largest N-heterocyclic carbene (NHC) to date for [Pd(NHC)(cin)Cl] complexes, explaining the high reactivity observed for this complex in this challenging transformation.

Polyporous metal-coordination frameworks.

Starting from a chiral building block--α-cyclodextrin--and rubidium salts, the crystallization of a complex of chiral helices, which constitute a "green" porous coordination polymer, has been realized. Cyclodextrin molecules coordinated by rubidium ions form porous, infinitely long left-handed helical channels, interdigitated with each other. A theoretical examination of the potential of this new material to act as a medium for chiral separation is presented.

Synthesis and biological characterisation of sirtuin inhibitors based on the tenovins.

The tenovins are small molecule inhibitors of the NAD(+)-dependent family of protein deacetylases known as the sirtuins. There remains considerable interest in inhibitors of this enzyme family due to possible applications in both cancer and neurodegenerative disease therapy. Through the synthesis of novel tenovin analogues, further insights into the structural requirements for activity against the sirtuins in vitro are provided. In addition, the activity of one of the analogues in cells led to an improved understanding of the function of SirT1 in cells.