Unsymmetrical platinum(II) phosphido derivatives: oxidation and reductive coupling processes involving platinum(III) complexes as intermediates

Reaction of the trinuclear [NBu 4] 2[(R F) 2Pt(mu-PPh 2) 2Pt(mu-PPh 2) 2Pt(R F) 2] ( 1, R F = C 6F 5) with HCl results in the formation of the unusual anionic hexanuclear derivative [NBu 4] 2[{(R F) 2Pt(mu-PPh 2) 2Pt(mu-PPh 2) 2Pt(mu-Cl)} 2] ( 4, 96 e (-) skeleton) through the cleavage of two Pt-C 6F 5 bonds. The reaction of 4 with Tl(acac) yields the trinuclear [NBu 4][(R F) 2Pt(mu-PPh 2) 2Pt(mu-PPh 2) 2Pt(acac)] ( 5, 48 e (-) skeleton), which is oxidized by Ag (+) to form the trinuclear compound [(R F) 2Pt(mu-PPh 2) 2Pt(mu-PPh 2) 2Pt(acac)][ClO 4] ( 6, 46 e (-) skeleton) in mixed oxidation state Pt(III)-Pt(III)-Pt(II), which displays a Pt-Pt bond. The reduction of 6 by [NBu 4][BH 4] gives back 5. The treatment of 6 with Br (-) (1:1 molar ratio) at room temperature gives a mixture of the isomers [(PPh 2R F)(R F)Pt(mu-PPh 2)(mu-Br)Pt(mu-PPh 2) 2Pt(acac)], having Br trans to R F ( 7a) or Br cis to R F ( 7b), which are the result of PPh 2/C 6F 5 reductive coupling. The treatment of 5 with I 2 (1:1 molar ratio) yields the hexanuclear [{(PPh 2R F)(R F)Pt(mu-PPh 2)(mu-I)Pt(mu-PPh 2) 2Pt(mu-I)} 2] ( 8, 96 e (-) skeleton), which is easily transformed into the trinuclear compound [(PPh 2R F)(R F)Pt(mu-PPh 2)(mu-I)Pt(mu-PPh 2) 2Pt(I)(PPh 3)] ( 9, 48 e (-) skeleton). Reaction of [(R F) 2Pt(mu-PPh 2) 2Pt(mu-PPh 2) 2Pt(NCMe) 2] ( 10) with I 2 at 213 K for short reaction times gives the trinuclear platinum derivative [(R F) 2Pt(mu-PPh 2) 2Pt(mu-PPh 2) 2Pt(I) 2] ( 11, 46e skeleton) in mixed oxidation state Pt(III)-Pt(III)-Pt(II) and with a Pt-Pt bond, while the reaction at room temperature and longer reactions times gives 8. The structures of the complexes have been established by multinuclear NMR spectroscopy. In particular, the (195)Pt NMR analysis, carried out also by (19)F- (195)Pt heteronuclear multiple-quantum coherence, revealed an unprecedented shielding of the (195)Pt nuclei upon passing from Pt(II) to Pt(III). The X-ray diffraction structures of complexes 4, 5, 6, 9, and 11 have been studied. A detailed study of the relationship between the complexes has been carried out.     

Determination of Intact Parabens in the Human Plasma of Cancer and Non-Cancer Patients Using a Validated Fabric Phase Sorptive Extraction Reversed-Phase Liquid Chromatography Method with UV Detection

Parabens have been widely employed as preservatives since the 1920s for extending the shelf life of foodstuffs, medicines, and daily care products. Given the fact that there are some legitimate concerns related to their potential multiple endocrine-disrupting properties, the development of novel bioanalytical methods for their biomonitoring is crucial. In this study, a fabric phase sorptive extraction reversed-phase liquid chromatography method coupled with UV detection (FPSE-HPLC-UV) was developed and validated for the quantitation of seven parabens in human plasma samples. Chromatographic separation of the seven parabens and p-hydroxybenzoic acid was achieved on a semi-micro Spherisorb ODS1 analytical column under isocratic elution using a mobile phase containing 0.1% (v/v) formic acid and 66% 49 mM ammonium formate aqueous solution in acetonitrile at flow rate 0.25 mL min⁻¹ with a 24-min run time for each sample. The method was linear at a concentration range of 20 to 500 ng mL⁻¹ for the seven parabens under study in human plasma samples. The efficiency of the method was proven with the analysis of 20 human plasma samples collected from women subjected to breast cancer surgery and to reconstructive and aesthetic breast surgery. The highest quantitation rates in human plasma samples from cancerous cases were found for methylparaben and isobutylparaben with average plasma concentrations at 77 and 112.5 ng mL⁻¹. The high concentration levels detected agree with previous findings for some of the parabens and emphasize the need for further epidemiological research on the possible health effects of the use of these compounds.     

Phonon-driven exciton dissociation at donor-acceptor polymer heterojunctions: direct versus bridge-mediated vibronic coupling pathways

We present a molecular-level, quantum dynamical analysis of phonon-driven exciton dissociation at polymer heterojunctions, using a linear vibronic coupling model parametrized for 3 electronic states and 24 vibrational modes. Quantum dynamical simulations were carried out using the multiconfiguration time-dependent Hartree method. In this study, which significantly extends the two-state model of Tamura et al. (Tamura, H.; Bittner, E. R.; Burghardt, I. J. Chem. Phys. 2007, 126, 021103), we focus on the role of bridge states, which can mediate the decay of the photogenerated exciton and possibly interfere with the direct transition toward an interfacial charge-separated state. Both the direct and bridge-mediated pathways are found to depend critically on the dynamical interplay of high-frequency C=C stretch modes and low-frequency ring-torsional modes. The dynamical mechanism is interpreted in terms of a hierarchical electron-phonon model, leading to the identification of generalized reaction coordinates for the nonadiabatic process. Variation of the vibronic coupling model parameters in a realistic range provides evidence that the direct exciton decay pathway is not dynamically robust, and bridge-mediated pathways can become dominant. The ultrafast, coherent dynamics is of pronounced nonequilibrium character and cannot be modeled by conventional kinetic equations. The predicted femtosecond to picosecond decay times are consistent with time-resolved spectroscopic observations.     

Docking of noncompetitive inhibitors into dengue virus type 2 protease: understanding the interactions with allosteric binding sites

A group of flavanones and their chalcones, isolated from Boesenbergia rotunda L., were previously reported to show varying degrees of noncompetitive inhibitory activities toward Dengue virus type 2 (Den2) protease. Results obtained from automated docking studies are in agreement with experimental data in which the ligands were shown to bind to sites other than the active site of the protease. The calculated K(i) values are very small, indicating that the ligands bind quite well to the allosteric binding site. Greater inhibition by pinostrobin, compared to the other compounds, can be explained by H-bonding interaction with the backbone carbonyl of Lys74, which is bonded to Asp75 (one of the catalytic triad residues). In addition, structure-activity relationship analysis yields structural information that may be useful for designing more effective therapeutic drugs against dengue virus infections.     

Mass spectrometry strategies applied to the characterization of proline-rich peptides from secretory parotid granules of pig (Sus scrofa)

Basic proline-rich proteins (bPRPs) are a class of proteins widely present in saliva of humans and other mammals. They are synthesized as preproproteins and enzymatically cleaved into small peptides before secretion from the salivary glands. Recently, we characterized two proline-rich peptides (SP-A and SP-B) in parotid secretory granules of pig (Sus Scrofa) that are derived from three isoforms of a PRP proprotein (Swiss-Prot data bank: Q95JC9-1, Q95JC9-2 and Q95JC9-3). Together the coding regions for SP-A and SP-B, which are repeated many times, account for 52-70% of the coding regions of the PRP proproteins. This study was undertaken to identify peptides encoded by unassigned regions of the PRP proproteins. RP-HPLC-ESI-IT-MS analysis of enriched granule preparations from pig parotid glands by two different analytical strategies identified ten new proline-rich peptides derived from the three proproteins. Together with the coding regions for SP-A and SP-B already identified it was possible to assign 68-75% of the proproteins coding regions. The peptide sequences indicated a number of unusual proteolytic cleavage sites suggesting the presence of unknown proprotein convertases.     

Optimization of a rapid capillary electrophoresis ESI-IT tandem mass spectrometry method for the analysis of short-chain carnitines in human plasma

A capillary electrophoresis (CE) method coupled to electrospray ionization ion trap tandem mass spectrometry (ESI-IT-MS/MS) is described for the rapid analysis of carnitine, acetylcarnitine, and propionylcarnitine in human plasma. Optimization of the procedure was achieved by a reduced sample pretreatment and after examining several physicochemical parameters that influence both the CE separation and the MS analytes detection. The analysis of total carnitine in human plasma after hydrolysis of short-chain metabolites is also shown. The analysis of carnitine and metabolites was obtained in less than 10 min using a 200 mM ammonium formate buffer, pH 2.5, with high sensitivity and specificity using the MS detection in product ion scan mode. The method was tested for quantitative recovery using dialyzed human plasma as matrix and showed linearity in the concentrations ranges 20–160, 1–32, and 0.25–8 μM for carnitine, acetylcarnitine, and propionylcarnitine with (squared) correlation coefficients of 0.9984, 0.9995, and 0.9991, respectively. The intraday and intermediate analysis repeatability and accuracy are within 15% of relative standard deviation (RSD) at low, medium, and high concentration and within/or slight exceeding 20% at the lower limit of quantitation (LLOQ). The method is sensitive for determining carnitine and its metabolites in human plasma with high specificity.     

Potent HIV-1 protease inhibitors incorporating meso-bicyclic urethanes as P2-ligands: structure-based design, synthesis, biological evaluation and protein-ligand X-ray studies

Recently, we designed a series of novel HIV-1 protease inhibitors incorporating a stereochemically defined bicyclic fused cyclopentyl (Cp-THF) urethane as the high affinity P2-ligand. Inhibitor with this P2-ligand has shown very impressive potency against multi-drug-resistant clinical isolates. Based upon the -bound HIV-1 protease X-ray structure, we have now designed and synthesized a number of meso-bicyclic ligands which can conceivably interact similarly to the Cp-THF ligand. The design of meso-ligands is quite attractive as they do not contain any stereocenters. Inhibitors incorporating urethanes of bicyclic-1,3-dioxolane and bicyclic-1,4-dioxane have shown potent enzyme inhibitory and antiviral activities. Inhibitor (K(i) = 0.11 nM; IC(50) = 3.8 nM) displayed very potent antiviral activity in this series. While inhibitor showed comparable enzyme inhibitory activity (K(i) = 0.18 nM) its antiviral activity (IC(50) = 170 nM) was significantly weaker than inhibitor . Inhibitor maintained an antiviral potency against a series of multi-drug resistant clinical isolates comparable to amprenavir. A protein-ligand X-ray structure of -bound HIV-1 protease revealed a number of key hydrogen bonding interactions at the S2-subsite. We have created an active model of inhibitor based upon this X-ray structure.