Design, synthesis and evaluation of some 1,6-disubstituted-1H-benzo[d]imidazoles derivatives targeted PI3K as anticancer agents.

Phosphatidylinositol 3-kinase (PI3K) pathway regulates various cellular processes, such as proliferation, growth, autophagy and apoptosis. Class I PI3K is frequently mutated and overexpressed in a lot of human cancers and PI3K was considered as a target for therapeutic treatment of cancer. In this study, we designed and synthesized a series of 1,6-disubstituted-1H-benzo[d]imidazoles derivatives and evaluated their anticancer activity and the compound 8i was identified as a lead compound. Compound 8i with the most potent antiproliferative activity was selected for further biological mechanism. The PI3K kinase assay have shown potent efficiency against four subtypes of PI3K with an IC50 of 0.5-1.9 nM. Molecular docking showed a possible formation of H-bonding with essential amino acid residues. Meanwhile, western blot assay indicated that 8i inhibited cell proliferation via suppression of PI3K kinase activity and subsequently blocked PI3K/Akt pathway activation in HCT116 cells. In addition, 8i could inhibit the migration and invasion ability of HCT116 cells and could induce apoptosis of HCT116 cells.

Stereoselective pharmacokinetics of 25-methoxyl-dammarane-3ß,12ß,20-triol and its active demethyl-metabolite epimers in rats after oral and intravenous administration.

Stereoselectivity of ginsenosides produced from the stereogenic carbon-20 has been proved to be closely related to drug action including pharmacodynamics and pharmacokinetics. 25-Methoxydammarane-3,12,20-triol (25-OCH3-PPD) and 25-hydoxyprotopanaxadiol (25-OH-PPD) are novel protopanaxadiol-type (PPD) sapogenins. 25-OH-PPD was also the in vivo bioactive demethyl-metabolite of 25-OCH3-PPD. The study aimed to investigate the influence of 20(R/S)-configuration on the pharmacokinetics of 20(R/S)-25-OCH3-PPD epimers and 20(R/S)-25-OH-PPD epimers. When rats were given 20(R/S)-25-OCH3-PPD epimers intravenously, the pharmacokinetic profiles of both epimers of 25-OCH3-PPD were similar, while the pharmacokinetic behaviors of their demethyl-metabolites were obviously different. After rats received an oral dose of 20(R/S)-25-OCH3-PPD epimers, the Cmax and AUC values of 20(S)-25-OCH3-PPD were at least 100 times higher than those of 20(R)-25-OCH3-PPD. Stereoselective pharmacokinetics of 25-OH-PPD was observed in rats after i.v. and i.g. administration of 20(R/S)-25-OH-PPD epimers. In vitro metabolic kinetics results indicated that faster hepatic metabolism of R-epimer should be one of the crucial factors accounting for the stereospecific pharmacokinetics of 25-OCH3-PPD and 25-OH-PPD epimers.

Identification and dynamic analysis of the purine alkaloids in rat plasma after oral administration of green tea by liquid chromatography hybrid ion trap time-of-flight mass spectrometry.

A liquid chromatography hybrid ion trap time-of-flight mass spectrometric (LC-IT-TOF-MS) method was developed and validated for identification and simultaneous determination of the potential bioactive components from green tea in rat plasma. The plasma samples were extracted by liquid-liquid extraction with ethyl acetate and separated on Shim-pack XR-ODS II column by a gradient elution within a runtime of 8.0 min. The mobile phase consisted of A (0.1% formic acid in acetonitrile) and B (0.1% formic acid in water) at a flow rate of 0.4 ml/min. Two prototype components and one metabolite were successfully identified as caffeine, theobromine and theophylline according to their retention times, accurate molecule weight, and major fragment ions. Then they were determined with the addition of two internal standards, hypoxanthine and paracetamol. The linear range was 10-10,000 ng/ml for caffeine, 2.0-2000 ng/ml for theobromine and 1.0-1000 ng/ml for theophylline, respectively. Intra-day and inter-day precision were within 6.0% and 10.9%, and accuracy was less than 4.8% and 6.5%, respectively. The validated method was successfully applied to investigate the dynamic change rules of caffeine, theobromine and theophylline in rat plasma after oral administration of caffeine, theobromine and green tea extract. The comparative analysis of the pharmacokinetic parameters indicated that there were obvious differences between green tea extract administration and single substances administration.