Mass spectrometric study of selected precursors and degradation products of chemical warfare agents.

Selected precursors and degradation products of chemical warfare agents namely N,N-dialkylaminoethane-2-ols, N,N-dialkylaminoethyl-2-chlorides and some of related N-quaternary salts were studied by means of electrospray ionization-multiple tandem mass spectrometry (ESI-MS(n)). Proposed structures were confirmed with accurate mass measurement. General fragmentation patterns of these compounds are discussed in detail and suggested processes are confirmed using deuterated standards. The typical processes are elimination of alkene, hydrogen chloride, or water, respectively. Besides, elimination of ethene from propyl chain under specific conditions was observed and unambiguously confirmed using exact mass measurement and labelled standard. The potential of mass spectrometry to distinguish the positional isomers occurring among the studied compounds is reviewed in detail using two different MS instruments (i.e. ion trap and hybrid quadrupole-time of flight (Q-TOF) analyzer). A new microcolumn liquid chromatography (microLC)/MS(n) method was designed for the cases where the resolution based solely on differences in fragmentation is not sufficient. Low retention of the derivatives on reversed phase (RP) was overcome by using addition of less typical ion pairing agent (1 mM/l, 3,5-dinitrobenzoic acid) to the mobile phase (mixture water : acetonitrile).

4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects.

In a routine screening of our small-molecule compound collection we recently identified 4-arylazo-3,5-diamino-1H-pyrazoles as a novel group of ATP antagonists with moderate potency against CDK2-cyclin E. A preliminary SAR study based on 35 analogues suggests ways in which the pharmacophore could be further optimized, for example, via substitutions in the 4-aryl ring. Enzyme kinetics studies with the lead compound and X-ray crystallography of an inhibitor-CDK2 complex demonstrated that its mode of inhibition is competitive. Functional kinase assays confirmed the selectivity toward CDKs, with a preference for CDK9-cyclin T1. The most potent inhibitor, 4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol 31b (CAN508), reduced the frequency of S-phase cells of the cancer cell line HT-29 in antiproliferation assays. Further observed cellular effects included decreased phosphorylation of the retinoblastoma protein and the C-terminal domain of RNA polymerase II, inhibition of mRNA synthesis, and induction of the tumor suppressor protein p53, all of which are consistent with inhibition of CDK9.

Synthesis and cytotoxic activity of substituted 2-phenyl-3-hydroxy-4(1H)-quinolinones-7-carboxylic acids and their phenacyl esters.

The preparation of 3-hydroxy-2-phenyl-4(1H)-quinolinones substituted in position 7 with a carboxyl group is described. The synthesis is based on the reaction of 2-aminoterephthalic acid with substituted alpha-bromoacetophenones and subsequent cyclization of the resulting bisphenacylesters in polyphosphoric acid. The reaction affords a mixture of substituted 3-hydroxy-2-phenyl-4(1H)-quinolinones 7-carboxylic acids as well as their phenacylesters. All quinolinones prepared (acids and phenacylesters) were tested for cytotoxic activity in vitro against five cancer cell lines and the results and a tentative structure-activity relationship are reported.

Cyclocondensation reaction of heterocyclic carbonyl compounds. Part XIII: synthesis and cytotoxic activity of some 3,7-diaryl-5-(3,4,5-trimethoxyphenyl)pyrazolo[4,3-e][1,2,4]triazines.

A series of the 3,7-diaryl-5-(3,4,5-trimethoxyphenyl)pyrazolo[4,3-e][1,2,4]triazines have been synthesized in five steps. The cytotoxic activity of all of the newly synthesized compounds has been tested in vitro against five cancer cell lines. Several compounds demonstrated significant broad cytotoxic activity in low micromolar range, while others were selectively active against lung adenocarcinoma cell line A549.

Capillary electrophoresis-mass spectrometry - a fast and reliable tool for the monitoring of milk adulteration.

The development of a rapid, simple and accurate analytical method aimed at the detection and quantification of bovine milk in either ovine or caprine milk samples by means of CE-MS analyses of whey proteins with high-ionic strength and presence of acidic running buffer is described. The high-ionic strength buffer was used in order to minimize the problems with the adsorption of the proteins onto the fused-silica capillary wall. The acidic running electrolyte, pH 1.9, was used to support the production of positive ions in electrospray. Highly linear dependences of the ratio of the sum of non-bovine beta-lactoglobulins (ovine or caprine) to the total beta-lactoglobulins in milk mixture (bovine plus ovine or bovine plus caprine) vs. the volume percentage of added bovine milk in ovine (or caprine) milk were obtained. This technique allowed the fast and reliable evaluation of milk adulteration. The amount of bovine milk added into the "non-bovine" ones can be well within the concentration range of 5-95%.

An anomalous course of the reduction of 2-(3-oxo-3,4-dihydroquinoxalin-2-yl)benzene diazonium salt: a reinvestigation.

The 1H,13C and 15N NMR spectra of the reduction product of 2-(3-oxo-3,4-dihydroquinoxalin-2-yl)benzene diazonium salt with sodium sulfite were measured and analysed. It is shown that the reaction product corresponds to 1-(indazol-3-yl)-1,2-dihydro-benzimidazol-2-on and not 6H-quinoxalino[1,2-c] [1,2,3]benzotriazin-12(13H)-one as published previously. The correctness of the structure was confirmed by an independent synthesis. The observed 15N chemical shifts were compared with the predicted ones using the ACD/NNMR 9.01 program.