Synthesis and properties of maleopimaric acid amides, imides and imidoamides with arylisoxazole and quinoline fragments

The method for maleopimaric acid N-(5-arylisoxazol-3-yl)amides synthesis has been developed by reaction of maleopimaric acid chloride with 3-amine-5-phenyl(4-methylphenyl)isoxazoles. N’-butyl-, N’-(2-hydroxyethyl)imides of maleopimaric acid N-(5-arylisoxazol-3-yl)amides were prepared. Heterocyclic imide – maleopimaric acid N-(quinolin-8-yl) imide was prepared by reaction of maleopimaric acid and 8-aminoquinoline in toluene at reflux in 97.1 % yield. It was established that refluxing of toluene solution of 8-aminoquinoline and maleated rosin, prepared by treatment of rosin with maleic anhydride and containing at least 50 % of maleopimaric acid, leads to the formation of maleopimaric acid N-(quinolin-8-yl)imide in 52.5 % yield (based on weight of maleated rosin). It was found by the methods of IR-, 1H NMR spectroscopy and mass-spectrometry that maleopimaric acid N-(quinolin-8-yl)imide consists of two diastereomeric atropisomers at 1:0.40 ratio. The biological properties of the prepared compounds were studied. It was established that maleopimaric acid N-(5-(4-methylphenyl)isoxazol-3-yl)amide possesses rotatory power (26 mkm-1) and may be used as chiral dopant to nematic LC for preparation of chiral LC-compositions.

Catalytic activity and stereoselectivity of engineered phosphotriesterases towards structurally different nerve agents in vitro

Highly toxic organophosphorus nerve agents, especially the extremely stable and persistent V-type agents such as VX, still pose a threat to the human population and require effective medical countermeasures. Engineered mutants of the Brevundimonas diminuta phosphotriesterase (BdPTE) exhibit enhanced catalytic activities and have demonstrated detoxification in animal models, however, substrate specificity and fast plasma clearance limit their medical applicability. To allow better assessment of their substrate profiles, we have thoroughly investigated the catalytic efficacies of five BdPTE mutants with 17 different nerve agents using an AChE inhibition assay. In addition, we studied one BdPTE version that was fused with structurally disordered PAS polypeptides to enable delayed plasma clearance and one bispecific BdPTE with broadened substrate spectrum composed of two functionally distinct subunits connected by a PAS linker. Measured kcat/KM values were as high as 6.5 and 1.5 × 108 M−1 min−1 with G- and V-agents, respectively. Furthermore, the stereoselective degradation of VX enantiomers by the PASylated BdPTE-4 and the bispecific BdPTE-7 were investigated by chiral LC–MS/MS, resulting in a several fold faster hydrolysis of the more toxic P(−) VX stereoisomer compared to P(+) VX. In conclusion, the newly developed enzymes BdPTE-4 and BdPTE-7 have shown high catalytic efficacy towards structurally different nerve agents and stereoselectivity towards the toxic P(−) VX enantiomer in vitro and offer promise for use as bioscavengers in vivo.

Quantitation of ivosidenib in human plasma via LC–MS/MS and its application in clinical trials

Aim: Ivosidenib is a potent and selective small molecule inhibitor of mutant isocitrate dehydrogenase 1. Accurate measurement of ivosidenib is the key to ivosidenib pharmacokinetics in clinical trials. Materials & methods: Quantitation of ivosidenib was conducted by using a stable isotope labeled compound (ivosidenib-d4) as the internal standard. Results: This assay was validated and successfully applied to support multiple clinical trials. Selected clinical samples were also tested by a chiral LC–MS/MS method against four ivosidenib isomer standards to exclude the possibility of in vivo racemization of ivosidenib. Conclusion: A robust LC–MS/MS method was validated for ivosidenib in human plasma. This is the first time for ivosidenib bioanalytical method in any human matrix to be reported.

Solid phase extraction procedure coupled with the chiral LC-ESI-MS/MS method for the enantioseparation and determination of butoconazole enantiomers in rat plasma and tissues: application to the enantioselective study on pharmacokinetics and tissue distribution

A significant enantioselective difference between (−)- and (+)-butoconazole existed in the stage of not only pharmacokinetics but also tissue distribution.

Evidence for Proteogenic Peptide-like Sequences in Meteorites Through an Enzyme-Catalysed Stereoselective Hydrolysis Strategy

In this manuscript, we evidenced for the first time proteogenic like peptide sequences in meteorite thanks to an original stereoselective enzymatic hydrolysis. Within this framework, we have first characterised the amino acids content of two meteorites, Murchison and Allende, after the standard acid hydrolysis protocol currently used in astronomical studies. To reach this goal, we have developed a highly sensitive chiral LC-MS method and we have highlighted new l- and d-enantiomers, never detected before in both meteorites. These primary findings extend the list of amino acids already found in meteorites. We next investigated the presence of proteogenic like peptide sequences. For that, we have compared the amounts of amino acids l- and d-enantiomers released from either the standard acid hydrolysis or our stereoselective peptidase hydrolysis. Thanks to this strategy, we have highlighted the presence of peptide sequences involving proteogenic l-amino acids in the Murchison together with their absence in Allende, which is consistent with the respective organic content of both meteorites. Furthermore, we demonstrated that the peptide sequences were indigenous to the Murchison meteorite.<br>

Evidence for Proteogenic Peptide-like Sequences in Meteorites Through an Enzyme-Catalysed Stereoselective Hydrolysis Strategy

In this manuscript, we evidenced for the first time proteogenic like peptide sequences in meteorite thanks to an original stereoselective enzymatic hydrolysis. Within this framework, we have first characterised the amino acids content of two meteorites, Murchison and Allende, after the standard acid hydrolysis protocol currently used in astronomical studies. To reach this goal, we have developed a highly sensitive chiral LC-MS method and we have highlighted new l- and d-enantiomers, never detected before in both meteorites. These primary findings extend the list of amino acids already found in meteorites. We next investigated the presence of proteogenic like peptide sequences. For that, we have compared the amounts of amino acids l- and d-enantiomers released from either the standard acid hydrolysis or our stereoselective peptidase hydrolysis. Thanks to this strategy, we have highlighted the presence of peptide sequences involving proteogenic l-amino acids in the Murchison together with their absence in Allende, which is consistent with the respective organic content of both meteorites. Furthermore, we demonstrated that the peptide sequences were indigenous to the Murchison meteorite.<br>