Design, synthesis, and primary activity assays of baicalein derivatives as cyclin-dependent kinase 1 inhibitors.

Malignant tumor is a disease with high mortality. Traditional treatment methods have many disadvantages, such as side-effects, drug resistance. Because cyclin-dependent kinase 1 (CDK1) plays an indispensable role in cell cycle regulation, it became an attractive target in rational anti-cancer drug discovery. Herein, we reported a series of baicalein derivatives, which remarkably repressed the proliferation of MCF-7 tumor cells and the activity of CDK1/cyclin B kinase. Among them, compound 4a displayed better inhibition rate than flavopiridol against MCF-7 proliferation at the concentration of 50 µg/ml, comparable to compound CGP74514A, while compound 3o possessed the best activity against CDK1/cyclin B kinase (IC50  = 1.26 µM). The inhibitory activities toward the kinase well correlated with anti-proliferative activities. Molecular docking results suggested that compound 3o can interact with the key amino acid residues, E81, L83, and D146, of CDK1 through hydrogen bond just like flavopiridol does. And it can also form an extra hydrogen bond with D146 by its introduced 7-acrylate group, which flavopiridol does not have. These findings proved that baicalein derivatives can be used as CDK1 inhibitors fighting against cancer.

Inhibitors of Cyclin-Dependent Kinase 1/2 for Anticancer Treatment.

BACKGROUND: The cell cycle is regulated by cyclin-dependent kinases (CDKs) and their cognate cyclins, along with their endogenous inhibitors (CDKIs). CDKs act as central regulators in this process. Different CDKs play relevant roles in different phases. Among all CDKs, CDK1 is indispensible, which can drive all events that are required in the cell cycle in the absence of interphase CDKs (CDK2, CDK3, CDK4 and CDK6). So, CDK1 is an attractive target for anticancer drug development. METHODS: CDK1 and CDK2 have 89.19% similar residues and 74.32% identical residues, their structures especially the ATP-binding sites are of great similarity. So, it is difficult to inhibit CDK1 and CDK2 individually. In this review, recent advances about CDK1/2 inhibitors were summarized. The chemical structures of different classes of CDK1/2 inhibitors and their structure activity are presented. RESULTS: 19 kinds of CDK1/2 or CDK1 inhibitors with different scaffolds, including CDK2 allosteric inhibitors, were summarized. Some inhibitors are nature derived, for example, phenanthrene derivatives, nortopsentin derivatives, variolin B derivatives and meridians. CONCLUSION: Nature products, especially marine ones are potential resources for CDK1 inhibitors development. The findings of CDK2 allosteric inhibitors open an avenue to the discovery of novel selective CDK1 or other CDKs allosteric inhibitors.

Assay development for determination of DZ2002, a new reversible SAHH inhibitor, and its acid metabolite DZA in blood and application to rat pharmacokinetic study.

Methyl (S)-4-(6-amino-9H-purin-9-yl)-2-hydroxybutanoate (DZ2002) is a potent reversible inhibitor of S-adenosyl-L-homocysteine hydrolase (SAHH). Due to its ester structure, DZ2002 is rapidly hydrolyzed in rat blood to 4-(6-amino-9H-purin-9-yl)-2-hydroxybutyric acid (DZA) during and after blood sampling from rats; this hampers accurate determination of the circulating DZ2002 and its acid metabolite DZA in rats. To this end, a method for determining the blood concentrations of DZ2002 and DZA in rats was developed by using methanol to immediately deactivate blood carboxylesterases during sampling. The newly developed bioanalytical assay possessed favorable accuracy and precision with lower limit of quantification of 31 nM for DZ2002 and DZA. This validated assay was applied to a rat pharmacokinetic study of DZ2002. After oral administration, DZ2002 was found to be extensively converted into DZA. The level of systemic exposure to DZ2002 was significantly lower than that of DZA. The apparent oral bioavailability of DZ2002 was 90%-159%. The mean terminal half-lives of DZ2002 and DZA were 0.3-0.9 and 1.3-5.1 h, respectively. The sample preparation method illustrated here may be adopted for determination of other circulating ester drugs and their acid metabolites in rodents.