title: Synthesis and Biological Evaluation of Scutellaria Flavone Cyclaneaminol Mannich Base Derivatives as Novel CDK1 Inhibitors.
abstract: Cyclin-dependent kinase 1 (CDK1) is the only necessary CDK in the cell proliferation process and a new target in the research and development of anti-cancer drugs. Natural flavones are selective CDK1 inhibitors which can suppress the proliferation of cancer cells. However, their bioavailability is poor. To solve these problems, 6 Scutellaria flavones were isolated from hydrolyzed products of Scutellaria baicalensis and used as lead compounds, 18 Scutellaria flavones cyclane-aminol Mannich base derivatives were semi-synthesized and their biological activity as novel CDK1 inhibitors was evaluated. Results indicated that the biological activity of 8-Hydroxypiperidinemethyl-baicalein (BA-j) is the highest among these compounds. BA-j is a selective CDK1 inhibitor, and has broad-spectrum anti-proliferative activity in human cancer cells (IC50 12.3μM). BA-j can capture oxygen free radicals (.O2(-)) and selectively increase intracellular H2O2 level in cancer cells and activated lymphocytes, thus inducing their apoptosis rather than in normal cells. These findings suggest that BA-j selectively induces apoptosis in cancer and activated lymphocyte by controlling intracellular H2O2 level, and can be developed into a novel anti-proliferative agent for the treatment of cancer, AIDS, and some immune diseases.
authors.forename: Lisha
authors.initials: L
authors.lastname: Ha
authors.forename: Yuan
authors.initials: Y
authors.lastname: Qian
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science & Technology, Dalian University of Technology, Linggong Road No.2, 116024, Dalian, Liaoning, China. zhangsx56@aliyun.com.
authors.forename: Shixuan
authors.initials: S
authors.lastname: Zhang
authors.forename: Xiulan
authors.initials: X
authors.lastname: Ju
authors.forename: Shiyou
authors.initials: S
authors.lastname: Sun
authors.forename: Hongmin
authors.initials: H
authors.lastname: Guo
authors.forename: Qianru
authors.initials: Q
authors.lastname: Wang
authors.forename: Kangjian
authors.initials: K
authors.lastname: Li
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Fan
authors.forename: Yang
authors.initials: Y
authors.lastname: Zheng
authors.forename: Hailiang
authors.initials: H
authors.lastname: Li
mesh_terms: D016203:CDC2 Protein Kinase; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047309:Flavones / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008352:Mannich Bases / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D031363:Scutellaria / Q000737:chemistry*
chemical_list: D047309:Flavones; D008352:Mannich Bases; D047428:Protein Kinase Inhibitors; D006861:Hydrogen Peroxide; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases