Dual-Functional abeo-Taxane Derivatives Destabilizing Microtubule Equilibrium and Inhibiting NF-kappa B Activation
Zhao, Yu1,2; Su, Jia1,3; Goto, Masuo2; Morris-Natschke, Susan L.2; Li, Yan1; Zhao, Qin-Shi1; Yao, Zhu-Jun4; Lee, Kuo-Hsiung2,5,6
2013-06-13
发表期刊JOURNAL OF MEDICINAL CHEMISTRY
ISSN0022-2623
卷号56期号:11页码:4749-4757
摘要Taxchinin A, with a 11(15 -> 1)-abeo-taxane skeleton, is a major, but inactive taxoid contained in leaves of Taxus chinensis. In our design of dual-functional antitumor abeo-taxane derivatives, two fragments from antitumor agents with different molecular targets (the N-acyl-3'-phenylisoserine side chain from the antimitotic agent paclitaxel and an alpha,beta-unsaturated carbonyl system from NF-kappa B inhibitors) were incorporated into the scaffold of taxchinin A. The resulting compounds displayed broad inhibitory effects against proliferation of tumor cell lines, with notable selectivity toward colon cancer, melanoma, and renal cancer, when evaluated in the NCI-60 human tumor cell line screening panel. On the basis of the NCI-60 assay data, structure-activity relationship (SAR) correlations were elucidated. Mechanistic studies indicated that this new compound type can both destabilize microtubules and inhibit NF-kappa B activation, thereby inducing tumor cell apoptosis. This first report of the dual-functional taxoid-core compounds thus provides new opportunities for future drug development based on natural axoid scaffolds.
关键词Natural-products Biological-activity Cancer-therapy Paclitaxel Taxol Resistance Drugs Chemotherapy Parthenolide Brevifoliol
资助信息National Natural Science Foundation of China [81172941, 21032002, 20802083, 90813004]; Ministry of Science and Technology [2011CB915503, 2009CB522303]; NIH from the National Cancer Institute [CA177584]
学科领域Chemistry, Medicinal
收录类别SCI ; IC
语种英语
WOS研究方向Pharmacology & Pharmacy
WOS类目Chemistry, Medicinal
WOS记录号WOS:000320640900042
引用统计
文献类型期刊论文
条目标识符http://ir.kib.ac.cn/handle/151853/16763
专题植物化学与西部植物资源持续利用国家重点实验室
作者单位1.Chinese Acad Sci, State Key Lab Phytochem & Plant Resources West Ch, Kunming Inst Bot, Kunming 650204, Peoples R China
2.Univ N Carolina, Nat Prod Res Labs, UNC Eshelman Sch Pharm, Chapel Hill, NC 27599 USA
3.Chinese Acad Sci, Grad Sch, Beijing 100039, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Bioorgan & Nat Prod Chem, EISU Chem Biol Div, Shanghai 200032, Peoples R China
5.Univ N Carolina, UNC Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA
6.China Med Univ & Hosp, Chinese Med Res & Dev Ctr, Taichung 40447, Taiwan
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Zhao, Yu,Su, Jia,Goto, Masuo,et al. Dual-Functional abeo-Taxane Derivatives Destabilizing Microtubule Equilibrium and Inhibiting NF-kappa B Activation[J]. JOURNAL OF MEDICINAL CHEMISTRY,2013,56(11):4749-4757.
APA Zhao, Yu.,Su, Jia.,Goto, Masuo.,Morris-Natschke, Susan L..,Li, Yan.,...&Lee, Kuo-Hsiung.(2013).Dual-Functional abeo-Taxane Derivatives Destabilizing Microtubule Equilibrium and Inhibiting NF-kappa B Activation.JOURNAL OF MEDICINAL CHEMISTRY,56(11),4749-4757.
MLA Zhao, Yu,et al."Dual-Functional abeo-Taxane Derivatives Destabilizing Microtubule Equilibrium and Inhibiting NF-kappa B Activation".JOURNAL OF MEDICINAL CHEMISTRY 56.11(2013):4749-4757.
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