Development and validation of a liquid chromatography–tandem mass spectrometry analytical method for the therapeutic drug monitoring of eight novel anticancer drugs

To support therapeutic drug monitoring of patients with cancer, a fast and accurate method for simultaneous quantification of the registered anticancer drugs afatinib, axitinib, ceritinib, crizotinib, dabrafenib, enzalutamide, regorafenib and trametinib in human plasma using liquid chromatography tandem mass spectrometry was developed and validated. Human plasma samples were collected from treated patients and stored at −20°C. Analytes and internal standards (stable isotopically labeled analytes) were extracted with acetonitrile. An equal amount of 10 mm NH₄CO₃ was added to the supernatant to yield the final extract. A 2 μL aliquot of this extract was injected onto a C₁₈‐column, gradient elution was applied and triple‐quadrupole mass spectrometry in positive‐ion mode was used for detection. All results were within the acceptance criteria of the latest US Food and Drug Administration guidance and European Medicines Agency guidelines on method validation, except for the carry‐over of ceritinib and crizotinib. These were corrected for by the injection order of samples. Additional stability tests were carried out for axitinib and dabrafenib in relation to their reported photostability. In conclusion, the described method to simultaneously quantify the eight selected anticancer drugs in human plasma was successfully validated and applied for therapeutic drug monitoring in cancer patients treated with these drugs.     

Cyanosilylation of aldehydes catalyzed by a porous metal-organic framework containing a coordinatively unsaturated Zn(II) center and its anticancer activity in human osteogenic sarcoma

Abstract

Solvothermal reaction of Zn(NO₃) · 6H₂O with the tripodal ligand 1,3,5-tris(4-carboxyphenyl)benzene (H₃BTB) afforded a highly porous metal-organic framework (MOF) {[Zn₃(BTB)₂(H₂O)₂] · 7DMF}_n (1). The resulting activated 1a exhibits BET surface areas of 1021?m² g^?1 with a pore size distribution around 11.8?Å, which was further applied in the cyanosilylation of aldehydes under solvent-free conditions. The experimental results show that, using 1a as the catalyst, both aliphatic and aromatic aldehydes were efficiently transformed to cyanohydrin trimethylsilyl ether. Meanwhile, significant size selectivity and electronic effects have also been observed. Then, we evaluated the anticancer activity of the synthesized compound 1a on six different kinds of cancer cell lines, including HeLa, CHO, HepG2, MG-63, MAD-MB-435, and BEAS-2B. CCK-8 results indicated 1a showed excellent inhibitory effect on cell proliferation, especially on the MG-63 human osteogenic sarcoma cells. Next, a transwell assay was performed to detect the migration and invasion activity of MG-63 cells after compound 1a treatment.     

Synthesis and structure of a 1-D copper(II) coordination polymer bridged both by oxamido and carboxylate: in vitro anticancer activity and reactivity toward DNA and protein BSA

A 1-D copper(II) coordination polymer formulated as {[Cu₂(bdpox)(dabt)](NO₃)·H₂O}_n, where H₃bdpox and dabt denote N-benzoate-N′-[3-(diethylamino)propyl]oxamide and 2,2′-diamino-4,4′-bithiazole, respectively, was synthesized and characterized by elemental analyses, molar conductance measurement, IR and electronic spectra studies, and single-crystal X-ray diffraction. The crystal structure analysis reveals that copper(II) ions are bridged by both cis-oxamido and carboxylato groups to form a 1-D coordination polymer with corresponding Cu···Cu separations of 5.2420(10) and 5.1551(8) Å. The endo- and exo-copper(II) ions of the cis-oxamido-bridge are located in distorted square-planar and square-pyramidal geometries, respectively. There is a 2-D hydrogen bonding network in the crystal. The in vitro anticancer activities suggest that the copper(II) complex is active against selected tumor cell lines. The reactivities toward herring sperm DNA and bovine serum albumin (BSA) reveal that the copper(II) complex can interact with DNA by intercalation and effectively quench the intrinsic fluorescence of BSA via a static mechanism. The influence of hydrophobicity of the substituents in bridging ligands on DNA and protein binding properties and the in vitro anticancer activities of such copper(II) polymers is discussed.     

On the influence of data noise and uncertainty on ordering of objects,described by a multi‐indicator system. A set of pesticides as an exemplary case

A priori in partial ordering methodology the input data are understood as exact and true values, which is denoted as the “original data matrix”. As such even minor differences between values are regarded as real. However, in real life data are typically associated with a certain portion of noise or uncertainty. Hence, introducing noise may cause changes in the overall ordering of objects. The present paper deals with the effects of data noise or uncertainties on the partial ordering of a series of objects, a series of obsolete pesticides being used as an illustrative example. The approach is fuzzy like, and partially ordered sets are obtained as function of noise. A main focus of the work is to identify the range in terms of noise, where the original partial order is retained. We call this range the “stability range”. It is demonstrated that by increasing data noise the range where the “original partial order” is obtained decreases. The original partial order is based on the original data matrix. Further, it is found that significant changes in the partial ordering appear outside of this stability range. The possible relation between data noise and the stability range is discussed on an empirical basis. Copyright © 2015 John Wiley & Sons, Ltd.     

Characterization of forsythoside A metabolites in rats by a combination of UHPLC‐LTQ‐Orbitrap mass spectrometer with multiple data processing techniques

Forsythoside A (FTA), the main active constituent isolated from Fructus Forsythiae, has various biological functions including anti‐oxidant, anti‐viral and anti‐microbial activities. However, while research on FTA has been mainly focused on the treatment of diseases on a material basis, FTA metabolites in vivo have not been comprehensively evaluated. Here, a rapid and sensitive method using a UHPLC‐LTQ‐Orbitrap mass spectrometer with multiple data processing techniques including high‐resolution extracted ion chromatograms, multiple mass defect filters and diagnostic product ions was developed for the screening and identification of FTA metabolites in rats. As the result, a total of 43 metabolites were identified in biological samples including 42 metabolites in urine, 22 metabolites in plasma and 15 metabolites in feces. These results demonstrated that FTA underwent a series of in vivo metabolic reactions including methylation, dimethylation, sulfation, glucuronidation, diglucuronidation, cysteine conjugation and their composite reactions. The research enhanced our understanding of FTA metabolism and built a foundation for further toxicity and safety studies.     

Metabolic profile of rosmarinic acid from Java tea (Orthosiphon stamineus) by ultra‐high‐performance liquid chromatography coupled to quadrupole‐time‐of‐flight tandem mass spectrometry with a three‐step data mining strategy

Rosmarinic acid (RA) is a caffeic acid derivative and one of the most abundant and bioactive constituents in Java tea (Orthosiphon stamineus), which has significant biological activities. However, relatively few studies have been conducted to describe this compound's metabolites in vivo. Therefore, an ultra‐high‐performance liquid chromatography coupled to quadrupole‐time‐of‐flight tandem mass spectrometry (UHPLC–QTOF–MS/MS) analysis with a three‐step data mining strategy was established for the metabolic profile of RA. Firstly, the exogenously sourced ions were filtered out by the MarkerView software and incorporated with Microsoft Office Excel software. Secondly, a novel modified mass detects filter strategy based on the predicted metabolites was developed for screening the target ions with narrow, well‐defined mass detection ranges. Thirdly, the diagnostic product ions and neutral loss filtering strategy were applied for the rapid identification of the metabolites. Finally, a total of 16 metabolites were reasonably identified in urine, bile and feces, while metabolites were barely found in plasma. The metabolites of RA could also be distributed rapidly in liver and kidney. Glucuronidation, methylation and sulfation were the primary metabolic pathways of RA. The present findings might provide the theoretical basis for evaluating the biological activities of RA and its future application.