Druggability Of CDK1 Inhibitors Wogonin Mannich Base Derivatives

Cyclin-dependent kinases (CDKs), the core of the cell cycle regulation, play an important role in cellular proliferation and have been reported as new attractive therapeutic targets for cancer and AIDS therapy. CDKs inhibitors, especially natural flavonoids, have become a research hotspot for anti-cancer drugs. Wogonin has strong inhibitory activity against various tumors as a natural CDK1 inhibitor. However, it has poor solubility, and can be excreted from the body by glucuronidation rapidly. So it is difficult for Wogonin to meet the clinical requirements because of the low blood concentration and low bioavailability.The druggability, including solubility, lipid-water partition coefficient, plasma protein binding rate and pharmacokinetics and tissue distribution of nitrogen-containing wogonin derivatives 6-hydroxypiperidine-methyl-wogonin (WA-j),6-(4-hydroxyethylpiperazine)-methyl-wogonin (WA-i) and 6-diethanolamine-methyl-wogonin (WA-e) was studied. The results showed that the solubility in PBS of WA-j, WA-i and WA-e were 42-,696- and 66-fold more than wogonin, respectively. Log P of WA-j, WA-i and WA-e in PBS was 0.91,0.94 and 1.41, respectively, much better than wogonin (2.80). The average plasma protein binding rates of WA-j and WA-i were 86.9% and 88.6%. Pharmacokinetics analysis suggested that WA-j was best fitted to a two-compartment model and WA-i was best fitted to a two-compartment model following a single oral administration, with the elimination half-life t1-2 (β) of 5.1 h and 3.3 h respectively. Tissue distribution test indicated that WA-j showed no special affinity to any tissue and no cumulative toxicity in vivo. The main metabolites were M573Ⅰand M573Ⅱafter a single or multiple oral administration of WA-j. It was found that product of hydrogenated reduction and degradation existed in metabolic pathways after multiple oral administrations. It was suggested that the mechanism of these drugs inducing tumor cell apoptosis preferentially was related to the selective increase of reactive oxygen species (ROS) concentration in tumor cells through the metabolic process of hydrogenated degradation.Above all, WA-j, with good druggability, is a candidate for CDK1 inhibitors and expected to become a new anticancer drug. This investigation provides evidence for further studies of nitrogen-containing wogonin derivatives in preclinical studies.