A Highly Luminescent Tetrahydrocurcumin IrIII Complex with Remarkable Photoactivated Anticancer Activity

Curcumin has chemopreventative properties against a variety of tumours, but has poor bioavailability. Here, two new bis-cyclometallated iridium(III) complexes have been prepared, featuring the natural product curcumin (CUR) or its reduced form, tetrahydrocurcumin (THC), as bidentate, anionic O O-binding ligands. The iridium THC complex is highly luminescent in deoxygenated solution and efficiently generates singlet oxygen under aerated conditions, whereas in the CUR analogue, other non-radiative decay pathways are competitive. The complexes are rapidly taken up by a variety of human tumour cell lines from solutions of micromolar concentration. They show negligible cytotoxicity in the absence of irradiation. When briefly irradiated with visible light, Ir-THC becomes highly phototoxic, inducing rapid apoptosis within 2 h. The results show the high potential of such complexes as sensitizers in photodynamic therapy (PDT).     

Messages in molecules: ligand/cation coding and self-recognition in a constitutionally dynamic system of heterometallic double helicates

Double helicates are known to exhibit self-recognition characteristics determined by the coordination geometry of the metal involved as well as by the topicity of the ligands. Combining tridentate (terpyridine, T) or bidentate (bipyridine, B) subunits in a tritopic strand affords a set of ligands able to assemble by pairs to form double helicates, homo- or heterostranded, homo- or heterotopic, depending on the coordination properties of the metals involved. The four ligand strands, BBB, TTT, BBT, and TBT form constitutionally dynamic sets of double helicates with the metal ions Cu(I), Cu(II), and Zn(II); these helicates correspond to the correct coding of the BB, BT, and TT pairs for tetra-, penta-, and hexacoordinate Cu(I), Cu(II), and Zn(II) cations, respectively.     

Determination of Olanzapine in rat brain using liquid chromatography with coulometric detection and a rapid solid-phase extraction procedure

A sensitive and selective method was developed for the determination of the antipsychotic drug Olanzapine levels in rat brain tissue, based on HPLC with electrochemical detection. The analyses were carried out on a C8 reversed phase column (150 mm x 4.6 mm, 5 microm), using a mobile phase composed of methanol and a phosphate buffer (44.0 mM, pH 3.5), containing triethylamine (21:79, v/v), flowing at 1.2 mL min(-1). A high sensitivity coulometric detection analytical cell containing two flow-through low volume working electrodes was used: electrode 1 was set at +0.350 V and electrode 2 at -0.200 V. Olanzapine, administered to rats in different doses or in different times, was extracted from tissue homogenate of either the whole brain or specific areas (cortex, hyppocampus, nucleus striatum) with a rapid solid phase extraction procedure (SPE) on Oasis HLB cartridges. The method provided a high extraction yield of Olanzapine and internal standard (2-methylolanzapine) from brain tissue homogenate with absolute recovery values higher than 90.0%. The detector response was linear over a concentration range of 0.2-100.0 ng mL(-1) of Olanzapine. The limit of quantification (LOQ) was 0.2 ng mL(-1). Precision results, expressed by the intra-day and the inter-day relative standard deviation values, were satisfactory, better than 4.6%. Accuracy was satisfactory as well. This method proved to be suitable for the analysis of Olanzapine in rat brain tissues and for the study of distribution and pharmacokinetics of Olanzapine in rat brain after a single treatment with the antipsychotic drug.     

Labeling trees with a condition at distance two

An L(h,k)-labeling of a graph G is an integer labeling of vertices of G, such that adjacent vertices have labels which differ by at least h, and vertices at distance two have labels which differ by at least k. The span of an L(h,k)-labeling is the difference between the largest and the smallest label. We investigate L(h,k)-labelings of trees of maximum degree Δ, seeking those with small span. Given Δ, h and k, span λ is optimal for the class of trees of maximum degree Δ, if λ is the smallest integer such that every tree of maximum degree Δ has an L(h,k)-labeling with span at most λ. For all parameters Δ,h,k, such that h<k, we construct L(h,k)-labelings with optimal span. We also establish optimal span of L(h,k)-labelings for stars of arbitrary degree and all values of h and k.     

A simple route towards peptide analogues containing substituted (S)- or (R)-tryptophans

We investigated the Lewis acid-promoted Friedel-Crafts alkylation of indole and substituted indoles with dehydroalanine-containing dipeptides R-Xaa-Dha-OR¹. The reaction proceeded with modest to sufficient diastereoselectivity, and yields strongly varied depending on the Lewis acid selected. The substituent R¹ of the ester group revealed some impact on the preferential formation of (S)-Trp or (R)-Trp. We exploited the reaction to prepare different peptides containing substituted tryptophans. To test the efficacy of this method for preparing biologically relevant compounds, we synthesized two unprecedented analogues of endomorphin-1, the endogenous agonist of the μ-opioid receptor, having either (S)- or (R)-2-methyltryptophan in position 3.     

Screening for pharmaco‐toxicologically relevant compounds in biosamples using high‐resolution mass spectrometry: a ‘metabolomic’ approach to the discrimination between isomers

High‐resolution mass spectrometry (HRMS) enables the identification of a chemical formula of small molecules through the accurate measurement of mass and isotopic pattern. However, the identification of an unknown compound starting from the chemical formula requires additional tools: (1) a database associating chemical formulas to compound names and (2) a way to discriminate between isomers. The aim of this present study is to evaluate the ability of a novel ‘metabolomic’ approach to reduce the list of candidates with identical chemical formula. Urine/blood/hair samples collected from real positive cases were submitted to a screening procedure using ESI‐MS‐TOF (positive‐ion mode) combined with either capillary electrophoresis or reversed phase liquid chromatography (LC). Detected peaks were searched against a Pharmaco/Toxicologically Relevant Compounds database (ca 50 500 compounds and phase I and phase II metabolites) consisting of a subset of PubChem compounds and a list of candidates was retrieved. Then, starting from the mass of unknown, mass shifts corresponding to pre‐defined biotransformations (e.g. demethylation, glucuronidation, etc.) were calculated and corresponding mass chromatograms were extracted from the total ion current (TIC) in order to search for metabolite peaks. For each candidate, the number of different functional groups in the molecule was automatically calculated using E‐Dragon software (Talete srl, Milan, Italy). Then, the presence of metabolites in the TIC was matched with functional groups data in order to exclude candidates with structures not compatible with observed biotransformations (e.g. loss of methyl from a structure not bearing methyls). The procedure was tested on 108 pharmaco‐toxicologically relevant compounds (PTRC) and their phase I metabolites were detected in real positive samples. The mean list length (MLL) of candidates retrieved from the database was 7.01 ± 4.77 (median, 7; range, 1–28) before the application of the ‘metabolomic’ approach, and after the application it was reduced to 4.08 ± 3.11 (median 3, range 1–17). HRMS allows a much broader screening for PTRC than other screening approaches (e.g. library search on mass spectra databases). The ‘metabolomic’ approach enables the reduction of the list of candidate isomers. Copyright © 2009 John Wiley & Sons, Ltd.     

Investigation of the degradation behaviour of poly(ethylene glycol-co-d,l-lactide) copolymer

The aim was to investigate the degradation behaviour of poly(ethylene glycol-co-d,l-lactide) (PEG-d,l-PLA) multiblock copolymer, in bulk and as microspheres, in aqueous medium. The degradation behaviour of PLA homopolymers in bulk and microspheres was evaluated as comparison.Microsphere preparation was performed by the double emulsion solvent evaporation method. Physical-chemical characterization of the raw polymers and the microspheres was performed by nuclear magnetic resonance (NMR) and modulated differential scanning calorimetry (MDSC). Polymer molecular weight, before and after incubation in aqueous environment, was evaluated by GPC; water uptake and mass loss were determined gravimetrically.The presence of PEG segments inside PLA chains gave a characteristic spongy structure to the microspheres. A significant increase in polymer T_g values was found for the microsphere formulations compared to polymer in bulk. After 63 days of incubation in the aqueous environment, the PEG-d,l-PLA microspheres achieved an average M_w reduction of 47% compared to 20% for PLA microspheres. The corresponding M_w decrease of the polymers in bulk was significantly higher: 72% and 41% for PEG-d,l-PLA and PLA, respectively.The data show how the degradation behaviour of polymer in bulk in an aqueous environment is significantly different from the behaviour of the corresponding microspheres. These results highlight the importance of performing a thorough physical-chemical characterization on microsphere formulations.     

Mechanism of the oxidation of sulfides by dioxiranes: conformational mobility and transannular interaction in the oxidation of thianthrene 5-oxide

The detailed study of the oxidation of thianthrene 5-oxide (1) with methyl(trifluoromethyl)dioxirane (5b) in different solvents and in the presence of (18)O isotopic tracers is reported. Thianthrene 5-oxide (1) is a flexible molecule in solution, and this property allows for transannular interaction of the sulfoxide group with the expected zwitterionic 7 and hypervalent 10-S-4 sulfurane 9 intermediates formed in the oxidation and biases the course of the reaction toward the monooxygenation pathway.