| The pharmacological activities and side effect of enantiomers of chiral drugsmay be different. Nowadays development and production of optically pure drugs isthe trend of new drugs research. The availability of chiral analytical separationmethods is important in studying and understanding the pharmacokinetic processes,the pharmacological and toxicological effects and quality control of many drugs.In this thesis, the chiral separation of pioglitazone and dithiocarbamate,γ-substituted butenolide, indole compounds were studied in normal-phase HPLC byusing chiralpak IC and the mechanism of the enantioseparation was discussed.Dithiocarbamate compounds were measured for antitumour and antibacterialactivities in vitro and the difference in activities between two enatiomers wasinvestigated. The content determination method of pioglitazone enatiomers has beenestablished and the seteroselcetive phamacokinetics of pioglitazone enantiomers infemale and male rats have been studied and compared firstly.1. The separation and content determination of pioglitazone enantiomersHPLC methods have been developed for the enantioseparation of pioglitazoneon chiralpak IC chiral column under normal phase mode. The influences of organicsolvent, based additives, flow rate and column temperature on the enantiomericseparation were investigated. The two enantiomers of pioglitazone were wellseparated, and the mechanism of the enantioseparation was discussed. The optimizedmethod for determination of pioglitazone enantiomers was validated. The limits ofdetection (LOD) and quantification (LOQ) were0.15and0.50μg/mL for bothenantiomers, respectively. The linearity of the method was in the range of0.50~100μg/mL with r2=0.9999. The inter-and intra-day assay precision was less than6.70%(RSD) and the average recoveries was in the range of97.3~110.8%. The method wasapplied to the content determination of pioglitazone enantiomers.2. Determination of pioglitazone enatiomers and their stereoselectivepharmacokinetics in ratsA chiral HPLC method was developed for the determination of pioglitazone enantiomers in rat plasma. The method was used for the stereoselectivepharmacokinetic study of pioglitazone in rat after intragastric administration ofpioglitazone racemate. The results showed that the isomer2(the second elution peak)levels in plasma were always higher than the levels of isomer1(the first elutionpeak), The mean Cmax, AUC0-24and AUC0-∞values for isomer2were about2timesof those of isomer1. Since the differences between the pharmacokinetic parametersCmax, AUC0-24,AUC0-∞and CL/F were significantly (P<0.05), the disposition of thetwo enantiomers seems to be different. The mean Cmaxvalues for two enantiomers infemale rats were1.7and2.2times of those in male rats, respectively. The meanAUC0-24values for two enantiomers in female rats were1.8and2.3times of those inmale rats, respectively. These results showed that the disposition of pioglitazoneenantiomers in female and male rats seems to be different.3. Studies on enantioseparation and antitumour and antibacterial activitiesof dithiocarbamate compoundsThe chiral resolution of the dithiocarbamate compounds were studied onchiralpak IC chiral stationary phase and the influences of the mobile phasecomposition and ratio, flow rate and column temperature on the enantiomericseparation were investigated.3dithiocarbamate compounds got wellseparation. Alldithiocarbamate compounds and two enantiomers of the first compound weremeasured for antitumour and antibacterial activities in vitro. The mean IC50valuesfor (+)–pioglitazone against two human tumor cell lines (MCF-7、MGC-803) wereabout2times of those of ()–pioglitazone by the MTT method. The mean IC50values for ()–pioglitazone against Staphyloccocus aureus, Escherichia coli andStenotrophomonas maltophilia were about2times of those of (+)–pioglitazone,respectively. Results showed that the antitumour and antibacterial activities betweentwo enatiomers were different.4. Enantioseparation of substituted butenolide and the new indolecompounds in normal-phase HPLCThe chiral resolution of the new substituted butenolide and indole compoundswhich showed very strong in vitro inhibitory and antineoplastic activity were studiedon chiralpak IC chiral stationary phase. The influences of the mobile phase composition and ratio, flow rate and column temperature on the enantiomericseparation were investigated and the mechanism of the enantioseparation wasdiscussed.6fluconazole substituted butenolide compounds were well separated.3indole compounds were baseline resolution and the others were not baselineresolution, which showed that the enantioselectivity between the new indolecompounds and CSPs was low. |
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