| Protein kinases regulate many critical biological mechanisms, including metabolites and cell growth, proliferation, differentiation. Cyclin-dependent kinases (CDKs) play a critical part in the the cell cycle regulation, which control the start and end of the cell cycle. As a new therapeutic target, CDKs inhibitor is expected to become a new generation of anti-cancer drugs. Baicalein is a natural CDK1 inhibitor, but it has low solubility and low plasma concentration. With hydrophilic groups introduced in, Mannich base derivatives of baicalein have better solubility, and thus better biological activity.The druggability including solubility, oil-water partition coefficient, the average protein binding rates and pharmacokinetics properties of 8-((4-methylpiperazin-l-yl)-methyl)-baicalein (BA-f),8-((piperazin-l-yl)-methyl)-baicalein,8-((4-hydroxypiperidine-l-yl)-methyl)-baicalein (BA-j) and 8-((4-hydroxyethylpiperazin-1-yl)-methyl)-baicalein (BA-i) in rabbits were studied in the present investigation. The results showed that the solubility of BA-i was 51-fold more than baicalein, BA-j was 28.8-fold more than baicalein while BA-f was 2.5 less than baicalein. Log P of BA-f, BA-j and BA-i was 1.7,0.69 and 0.67, respectively, which were much better than baicalein. The average protein binding rates were 98.2%,91.8% and 97.6%. The pharmacolinetics analysis suggested that both BA-j and BA-i pharmacokinetics was best fitted to a two-compartment model following a single intravenous administration with the elimination half-life t1/2 (β) of 3.78 h and 4.23h respectively and the concentration at the steady state was 28.7μM and 31.6μM,1000 times higher than baicalein (0.026μM). Validated liquid chromatography/tandem mass spectrometry method was carried out for identification of BA-j metabolites. The main metabolites were M387 and M559. Tissue distribution test indicated that BA-j showed no special affinity to any tissues.The results showed that BA-j had the best druggability. This investigation might be beneficial contribution to further studies of mannich derivatives of baicalein in preclinical pharmacokinetic studies. |
