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论文类型：期刊论文

发表时间：2015-12-01

发表刊物：FITOTERAPIA

收录刊物：SCIE、PubMed、Scopus

卷号：107

页面范围：36-43

ISSN号：0367-326X

关键字：8-Hydroxypiperidine-methyl-baicalein (BA-j); Baicalein (BA); Anti-cancer drug; Pharmacokinetics CDK1 inhibitor; Peroxides (H2O2)

摘要：Cyclin-dependent kinase I (CDK1) is the only necessary CDK in the cell proliferation process and anew target in the research and development of anti-cancer drugs. 8-Hydroxypiperidinemethyl-baicalein (BA-j) is a Mannich base derivative of baicalein (BA) isolated from Scutellaria baicalensis, as a novel selective CDK1 inhibitor. 12 metabolites of BA-j in the monkey urine were identified by LC-MS-MS and H-1 NMR The major metabolic pathways of BA-j, by capturing oxygen free radicals (O-center dot(2)-) and releasing peroxides (H2O2), are degraded into active intermediate metabolite dihydroflavonol, then into main metabolite M179 by Shiff reaction, second metabolite M264 by sulfation, trace amount of metabolite M559 by glucuronidation UGT1A9, and without metabolism by CYP3A4. The metabolic process of BA-j by regulating intracellular reactive oxygen species (ROS) was related with BA-j selectively inducing apoptosis in cancer cells. Pharmacokinetics of 10 mg/kg oral BA-j in monkey by HPLC-UV was best fitted to a two-compartment open model, with t(1/2)(beta) of 4.2 h, C-max a 25.4 mu M at 2 h, and V-d 12.6 L, meaning the drug distributing widely in body fluids with no special selectivity to certain tissues, and being able to permeate through the blood-brain barrier. The protein binding rate of BA-j was 91.8%. BA-j has excellent druggability for oral administration or injection, and it may be developed into a novel anti-cancer drug as a selective CDK1 inhibitor. (C) 2015 Elsevier B.V. All rights reserved.