The development and validation of a novel LC–MS/MS method for the quantification of cenicriviroc in human plasma and cerebrospinal fluid

A high-performance liquid chromatography tandem mass spectrometric method was developed and validated for cenicriviroc (CVC) quantification in human plasma and cerebrospinal fluid (CSF). The method involved precipitation with acetonitrile and injecting supernatants onto the column. Separation was achieved on an XBridge C₁₈ column with a gradient elution of 0.1% formic acid in water and acetonitrile. Analyte detection was conducted in positive ion mode using selected reaction monitoring. The m/z transitions were: CVC (697.3 → 574.3) and CVC-d7 (704.4 → 574.3). Calibration curve ranged from 5 to 1000 ng/mL for plasma and from 0.241 to 15.0 ng/mL for CSF. The intra- and inter-day precision and accuracy were <15% for both plasma and CSF across four different concentrations. CVC recovery from plasma and artificial CSF was >90%. The method was utilized for the measurement of patients’ plasma and CSF samples taking a dose of 50, 150 and 300 mg q.d.     

High Activity and Selective Fischer–Tropsch Catalysts for Use in a Microchannel Reactor

Each process configuration for practicing the Fischer–Tropsch synthesis places demands particular to that configuration on the catalyst to be used. We discuss how a particular catalyst, prepared by the OMX (organic matrix combustion) method, when used in conjunction with the Velocys microchannel reactor system, results in a very stable, high performance Fischer–Tropsch synthesis system. With the ability to remove heat far more effectively than a conventional reactor system, this microchannel reactor requires a catalyst with much higher volumetric reactive site density. Further, with such a high volumetric reaction rate, mass transfer effects will be important in both the observed activity and selectivity of the operating catalyst. Nevertheless, the catalyst prepared using the OMX method exhibits an apparent turnover frequency which is considerably higher than reported for other catalysts in the literature. In addition to high activity, an economically useful catalyst must exhibit a stable, high selectivity for liquid products and be able to recover near-fresh performance using a regeneration approach which can be carried out with the catalyst in-place. An example of such a stable, multiply regenerated catalyst is given. Finally, further development has focused on a catalyst with even higher C₅₊ selectivity.     

Synthesis and Biological Evaluation of RGD Peptidomimetic–Paclitaxel Conjugates Bearing Lysosomally Cleavable Linkers

Two small‐molecule–drug conjugates (SMDCs, 6 and 7 ) featuring lysosomally cleavable linkers (namely the Val–Ala and Phe–Lys peptide sequences) were synthesized by conjugation of the α_vβ₃‐integrin ligand cyclo[DKP–RGD]‐CH₂NH₂ ( 2 ) to the anticancer drug paclitaxel (PTX). A third cyclo[DKP–RGD]–PTX conjugate with a nonpeptide “uncleavable” linker ( 8 ) was also synthesized to be tested as a negative control. These three SMDCs were able to inhibit biotinylated vitronectin binding to the purified α_Vβ₃‐integrin receptor at nanomolar concentrations and showed good stability at pH 7.4 and pH 5.5. Cleavage of the two peptide linkers was observed in the presence of lysosomal enzymes, whereas conjugate 8 , which possesses a nonpeptide “uncleavable” linker, remained intact under these conditions. The antiproliferative activities of the conjugates were evaluated against two isogenic cell lines expressing the integrin receptor at different levels: the acute lymphoblastic leukemia cell line CCRF‐CEM (α_Vβ₃?) and its subclone CCRF‐CEM α_Vβ₃ (α_Vβ₃+). Fairly effective integrin targeting was displayed by the cyclo[DKP–RGD]–Val–Ala–PTX conjugate ( 6 ), which was found to differentially inhibit proliferation in antigen‐positive CCRF‐CEM α_Vβ₃ versus antigen‐negative isogenic CCRF‐CEM cells. The total lack of activity displayed by the “uncleavable” cyclo[DKP–RGD]–PTX conjugate ( 8 ) clearly demonstrates the importance of the peptide linker for achieving the selective release of the cytotoxic payload.     

Electrochemical Sensing of Uric Acid Using Glassy Carbon Modified with Multiwall Carbon Nanotubes Dispersed in Polyethylenimine

This work reports the advantages of using glassy carbon electrodes modified with multiwall carbon nanotubes (MWCNT) dispersed in polyethylenimine (PEI). The presence of MWCNTs wrapped by PEI largely facilitated the strong adsorption of uric acid (UA) and allowed its highly sensitive and selective quantification even in the presence of high excess of ascorbic acid. The selected conditions for the electrochemical sensing were 5 s accumulation at ?0.300 V under stirring and quantification in a 0.050 M phosphate buffer solution pH 7.40 by differential pulse voltammetry adsorptive‐stripping after medium exchange. The platform allowed the successful application in the quantification of UA in urine.     

The Glycolytic Pathway as a Target for Novel Onco-Immunology Therapies in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal forms of human cancer, characterized by unrestrained progression, invasiveness and treatment resistance. To date, there are limited curative options, with surgical resection as the only effective strategy, hence the urgent need to discover novel therapies. A platform of onco-immunology targets is represented by molecules that play a role in the reprogrammed cellular metabolism as one hallmark of cancer. Due to the hypoxic tumor microenvironment (TME), PDA cells display an altered glucose metabolism—resulting in its increased uptake—and a higher glycolytic rate, which leads to lactate accumulation and them acting as fuel for cancer cells. The consequent acidification of the TME results in immunosuppression, which impairs the antitumor immunity. This review analyzes the genetic background and the emerging glycolytic enzymes that are involved in tumor progression, development and metastasis, and how this represents feasible therapeutic targets to counteract PDA. In particular, as the overexpressed or mutated glycolytic enzymes stimulate both humoral and cellular immune responses, we will discuss their possible exploitation as immunological targets in anti-PDA therapeutic strategies.     

Evidence for Non-Innocence of a β-Diketonate Ligand

β-Diketonates, such as acetylacetonate, are amongst the most common bidentate ligands towards elements across the entire periodic table and are considered wholly redox-inactive in their complexes. Herein we show that complexation of 1,1,1,5,5,5-hexafluoroacetylacetonate (hfac⁻) to Cr^II spontaneously affords Cr^III and a reduced β-diketonate radical ligand scaffold, as evidenced by crystallographic analysis, magnetic measurements, optical spectroscopy, reactivity studies, and DFT calculations. The possibility of harnessing β-diketonates as electron reservoirs opens up possibilities for new metal–ligand concerted reactivity in the ubiquitous β-diketonate coordination chemistry.     

Luminescent PtII and PtIV Platinacycles with Anticancer Activity Against Multiplatinum-Resistant Metastatic CRC and CRPC Cell Models

Platinum-based chemotherapy persists to be the only effective therapeutic option against a wide variety of tumours. Nevertheless, the acquisition of platinum resistance is utterly common, ultimately cornering conventional platinum drugs to only palliative in many patients. Thus, encountering alternatives that are both effective and non-cross-resistant is urgent. In this work, we report the synthesis, reduction studies, and luminescent properties of a series of cyclometallated (C,N,N′)Pt^IV compounds derived from amine–imine ligands, and their remarkable efficacy at the high nanomolar range and complete lack of cross-resistance, as an intrinsic property of the platinacycle, against multiplatinum-resistant colorectal cancer (CRC) and castration-resistant prostate cancer (CRPC) metastatic cell lines generated for this work. We have also determined that the compounds are effective and selective for a broader cancer panel, including breast and lung cancer. Additionally, selected compounds have been further evaluated, finding a shift in their antiproliferative mechanism towards more cytotoxic and less cytostatic than cisplatin against cancer cells, being also able to oxidize cysteine residues and inhibit topoisomerase II, thereby holding great promise as future improved alternatives to conventional platinum drugs.     

A Lie symmetry approach for the solution of the inverse kinematics problem

In this paper, it is considered the inverse kinematics problem, which is faced from a differential point of view. In particular, it is shown that an asymptotic inverse kinematics can be interpreted as a Lie symmetry of the direct kinematics. A parameterization of all Lie symmetries of the direct kinematics is proposed, and the classical Newton and gradient method are obtained as particular cases.     

A 1D Roe decomposition of a system of equations governing wave height transformation

A Roe‐type decomposition for a system of equations governing onshore/offshore wave transformation in coastal waters is derived. The equation set approximated pertains to coastal waters prior to wave breaking, and is based on depth‐averaging and time‐averaging of the Euler equations. The equations are those used in many commercial codes for simulation of wave height and wave‐averaged currents. This novel approach uses a combination of some standard Roe averages, together with physical reasoning and power series expansions to derive a Roe‐averaged Jacobian (with real, linearly independent eigenvectors) and ensures conservation, and thereby effects the decomposition. It is shown that the resulting derived Roe‐averaged quantities are accurate to a high degree, by comparing them with their analytical equivalents for a wide range of nondimensional water depths and slopes likely to be encountered in coastal problems. Numerical tests of time‐invariant wave height transformation and wave group propagation are undertaken; these indicate good performance of the scheme in practice. Copyright © 2011 John Wiley & Sons, Ltd.