Structural Modification of Natural Product Tanshinone I Leading to Discovery of Novel Nitrogen-Enriched Derivatives with Enhanced Anticancer Profile and Improved Drug-like Properties

doi:10.1021/acs.jmedchem.7b01259

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	Structural Modification of Natural Product Tanshinone I Leading to Discovery of Novel Nitrogen-Enriched Derivatives with Enhanced Anticancer Profile and Improved Drug-like Properties
	Ding, Chunyong1,2 ; Tian, Qianting 1,4; Li, Jie 2,3; Jiao, Mingkun 2; Song, Shanshan 4; Wang, Yingqing1,4 ; Miao, Zehong 1,4; Zhang, Ao1,2,3,4
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2018-02-08
卷号	61 期号:3 页码:760-776
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.7b01259
文献子类	Article
英文摘要	The clinical development of natural product tanshinone I (1) for cancer therapy is hampered by its weak potency and poor drug-like properties. Herein, a more broad and systemic structural modification on 1 was conducted to generate four series of new tanshinone derivatives. Among them, the lactam derivative 22h demonstrated the most potent antiproliferative activity against KB and drug-resistant KB/VCR cancer cells, which are approximately 13- to 49-fold more potent than 1. Compound 22h possesses significantly improved drug-like properties including aqueous solubility (15.7 mg/mL), metabolic stability of liver microsomes, and PK characters (T-1/2 = 2.58 h; F = 21%) when compared to 1. Preliminary mechanism studies showed that 22h significantly induced apoptosis of HCT116 cells, at least partially, through activation of caspase-3/-7. More importantly, administration of 22h at 10 mg/kg significantly suppressed the tumor growth of HCT116 xenograft in-vivo without significant loss of body weight of the tested nude mice.
资助项目	National Natural Science Foundation of China[81430080] ; National Natural Science Foundation of China[81373277] ; National Natural Science Foundation of China[81773565] ; National Natural Science Foundation of China[81402790] ; National Program on Key Basic Research Project of China[2015CB910603] ; International Cooperative Program[GJHZ1622 2060899] ; Key Program of the Frontier Science of the Chinese Academy of Sciences[QYZDJ-SSW-SMC002] ; Shanghai Commission of Science and Technology[16XD1404600] ; Shanghai Commission of Science and Technology[14431905300] ; Shanghai Commission of Science and Technology[14431900400]
WOS关键词	SALVIA-MILTIORRHIZA BUNGE ; PROSTATE-CANCER CELLS ; DIHYDROTANSHINONE-I ; MASS-SPECTROMETRY ; SIGNALING PATHWAY ; IIA ; CRYPTOTANSHINONE ; APOPTOSIS ; GROWTH ; MICE
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000425063400011
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279909]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室药物化学研究室
通讯作者	Wang, Yingqing; Miao, Zehong; Zhang, Ao
作者单位	1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Synthet Organ & Med Chem Lab, Shanghai 201203, Peoples R China; 3.ShanghaiTech Univ, Shanghai 20120, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Ding, Chunyong,Tian, Qianting,Li, Jie,et al. Structural Modification of Natural Product Tanshinone I Leading to Discovery of Novel Nitrogen-Enriched Derivatives with Enhanced Anticancer Profile and Improved Drug-like Properties[J]. JOURNAL OF MEDICINAL CHEMISTRY,2018,61(3):760-776.
APA	Ding, Chunyong.,Tian, Qianting.,Li, Jie.,Jiao, Mingkun.,Song, Shanshan.,...&Zhang, Ao.(2018).Structural Modification of Natural Product Tanshinone I Leading to Discovery of Novel Nitrogen-Enriched Derivatives with Enhanced Anticancer Profile and Improved Drug-like Properties.JOURNAL OF MEDICINAL CHEMISTRY,61(3),760-776.
MLA	Ding, Chunyong,et al."Structural Modification of Natural Product Tanshinone I Leading to Discovery of Novel Nitrogen-Enriched Derivatives with Enhanced Anticancer Profile and Improved Drug-like Properties".JOURNAL OF MEDICINAL CHEMISTRY 61.3(2018):760-776.