Synthesis and Biological Evaluation of Scutellaria Flavone Cyclaneaminol Mannich Base Derivatives as Novel CDK1 Inhibitors

Author(s):

Lisha Ha, Yuan Qian, Shixuan Zhang, Xiulan Ju, Shiyou Sun, Hongmin Guo, Qianru Wang, Kangjian Li, Qingyu Fan, Yang Zheng and Hailiang Li   Pages 914 - 924 ( 11 )

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.

Keywords:

8-hydroxypiperidine-methyl-baicalein (BA-j), anti-cancer drug, apoptosis, CDK1 inhibitor, peroxides (H₂O₂).

Affiliation:

, , State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science & Technology, Dalian University of Technology, Linggong Road No.2, 116024, Dalian, Liaoning, China.

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