Preparation And SAR Evaluation Of Scutellaria Flavonoids Mannich Base Derivatives As CDK1/Cyclin B Inhibitors

Cyclin-dependent kinases (CDKs) are specific serine/threonine protein kinases that play a key role in cell cycle regulation allowing transition between its different phases. It would result in an abnormal cell cycle and cell proliferation without control once CDKs missed or expressed disorderly, and ultimately resulted in tumor. A number of studies have revealed that overexpression of CDKs is tightly involved in more than 90% human tumor cell lines. CDKs have become potential targets for new drugs development in antitumor research. CDKs inhibitors have become a hot spot in antitumor drugs development. Among them, Flavonoids compounds are an important kind of CDKs inhibitors. Scutellaria baicalensis Georgi is one of the most popular traditional Chinese medicine herbs with a variety of pharmacology activities. Its main effective ingredients, Baicalein, Wogonin, and Oroxylin-A have been comfirmed to exert their cytostatic effects on tumor cells by inducing cell cycle arrest at several checkpoints depending on types of tumors while have no effect on normal cells. However, the clinical utilization of them is still limited because of their low activity and steady state plasma concentration, and poor solubility.In this paper, Baicalein, Wogonin, and Oroxylin-A were isolated from the dry root of Scutellaria baicalensis Georgi as lead compounds, Sixteen novel Mannich base derivatives were prepared as CDK1 inhibitors through introducing some nitrogen-containing groups onto the nucleus of the lead compounds by Mannich reaction. All the lead compounds and their derivatives in this paper were screened for the inhibitory activities of CDK1/Cyclin B using a FRET-based biochemical assay method. The structure-activity relationship was analyzed. The IC50 values of compounds BA-i, j, WA-i, j were at about 0.26-0.30μM, which were about 3-fold higher than P276-00, and at the same level as Flvopirdol. They would be preferable antitumor candidates.A simple preparing process was optimized using the orthogonal test method. The extraction ratio of this process was at about 90% and Baicalein was prepared with purity over 97%. The process is applied to industrialization easily.