Systematic Stereoselectivity Evaluations of Tetramethrin Enantiomers: Stereoselective Cytotoxicity, Metabolism, and Environmental Fate in Earthworms, Soils, Vegetables, and Fruits.

Tetramethrin is a widely applied type I chiral pyrethroid insecticide that exists as a mixture of four isomers. In the present study, its stereoselective cytotoxicity, bioaccumulation, degradation, and metabolism were investigated for the first time at the enantiomeric level in detail by using a sensitive chiral high-performance liquid chromatography-tandem mass spectroscopy (HPLC-MS/MS) method. Results showed that among rac-tetramethrin and its four enantiomers, the trans (+)-1R,3R-tetramethrin had the strongest inhibition effect on the PC12 cells. In the earthworm exposure trial, the concentration of trans (-)-1S,3S-tetramethrin was 0.94-8.92 times in earthworms (cultivated in natural soil) and 1.67-5.01 times (cultivated in artificial soil) higher than trans (+)-1R,3R-tetramethrin, respectively. In the greenhouse experiment, the trans (+)-1R,3R-tetramethrin and cis (+)-1R,3S-tetramethrin were preferentially degraded. Furthermore, for rat liver microsome in vitro incubation, the maximum metabolism rate of cis (-)-1S,3R-tetramethrin was 1.50 times higher than its antipodes. Altogether, the aim of this study was to provide a scientific and reasonable reference for the possibility of developing a single enantiomer to replace the application of rac-tetramethrin, which could possess better bioactivity and lower ecotoxicity, and thus permit more reliable and accurate environmental monitoring and risk assessment.

Development of a novel HPLC-ESI-MS/MS method to analyze the stereoselective pharmacokinetics and tissue distribution of isoconazole enantiomers in rats.

Isoconazole with an asymmetrical carbon is a broad-spectrum antimicrobial imidazole, but there is still lack of relevant report about the potential enantioselectivity in biological samples. The object of this research was to develop and validate a sensitive and effective high performance liquid chromatography-electrospray ionization coupled with tandem mass spectrometry (HPLC-ESI-MS/MS) method for stereoselective separation and determination of isoconazole enantiomers in Sprague-Dawley (SD) rat plasma and tissues. The greater enantioseparation of isoconazole enantiomers was obtained on a Chiralpak IC column with a mobile phase consisted of acetonitrile-10 mM aqueous ammonium acetate (90:10, v/v) under the reversed-phase mode. Subsequently, the studied compounds and internal standard (IS) were detected on a multiple reaction monitoring (MRM) mode with positive electrospray ionization source. The experimental and theoretical Electronic Circular Dichroism (ECD) spectra were employed to confirm the absolute configuration of isoconazole enantiomers. Eventually, after full method validation, the newly developed method was successfully applied to the study of enantioselectivity in plasma and tissues in SD rats. Results illustrated that the enantioselective differences in plasma were observed for the evidence that the concentrations of S-(-)-isoconazole were always higher than R-(+)-isomer. In terms of tissue distribution, liver, kidney, lung, spleen, and small intestine were the mainly distributed tissues and then followed by heart and muscle. This is the first study to reveal the stereoselective behavior of isoconazole enantiomers in vivo, which also provides reliable and valuable reference for further elucidating the enantioselective metabolisms of isoconazole enantiomers.

Anti-tumor activity of new artemisinin-chalcone hybrids.

In an attempt to develop potent and selective anti-tumor agents, three new series of artemisinin-chalcone hybrids 10a-10g, 11a-11g and 12a-12h were designed, synthesized and screened for their anti-tumor activity against five cell lines (HT-29, A549, MDA-MB-231, HeLa and H460) in vitro. Among compounds 10a-g and 11a-11g, most of them displayed enhanced activity and good selectivity toward HT-29 and HeLa cell lines with IC(50) values ranging from 0.12 to 0.85 µM as compared with DHA (dihydroartemisinin). Compounds 10a and 11a are most active toward HeLa cells with IC(50) values of 0.12 and 0.19 µM. The results revealed that the presence of chalcone moiety is beneficial to their activity and selectivity. In addition, compounds 12a-12h containing a 'reversed chalcone' moiety showed only slight improvement in activity than those of DHA.