Bicyclo[2.2.1]heptane containing N,N-diarylsquaramide CXCR2 selective antagonists as anti-cancer metastasis agents

doi:10.1039/c8ra01806e

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	Bicyclo[2.2.1]heptane containing N,N-diarylsquaramide CXCR2 selective antagonists as anti-cancer metastasis agents
	Che, Jin-Xin 1; Wang, Zhi-Long 3; Dong, Xiao-Wu 1; Hu, You-Hong3 ; Xie, Xin2,3 ; Hu, Yong-Zhou 1
刊名	RSC ADVANCES
	2018
卷号	8 期号:20 页码:11061-11069
ISSN号	2046-2069
DOI	10.1039/c8ra01806e
文献子类	Article
英文摘要	CXCR1 and CXCR2 are CXC chemokine receptors (CXCRs), corresponding to cytokines of the CXC chemokine family. CXCR2 was found to be 77% homologous to CXCR1. Antagonism of the chemokine receptor CXCR2 has been proposed as a new strategy for the treatment of metastatic cancer. In order to find a CXCR2 selective antagonist, a bicyclo[2.2.1]heptane containing N,N-diarylsquaramide (compound 2e) was identified by introducing a bridge ring system into the N,N-diarylsquaramide skeleton, and it exhibited good CXCR2 antagonistic activity ((IC50)-I-CXCR2 = 48 nM) and good selectivity ((IC50)-I-CXCR1/(IC50)-I-CXCR2 = 60.4). Furthermore, an in vitro biological assay of compound 2e also demonstrated its good anti-cancer metastatic effect against the pancreatic cancer cell line CFPAC1. In addition, compound 2e showed an extremely high stability in simulated intestinal fluid (SIF) and simulated gastric fluid (SGF), as well as in rat and human plasma, but not in rat and human liver microsomes. In vivo pharmacokinetic studies in rats indicated that 2e has an excellent PK profile (10 mg kg(-1) po, C-max = 2863 ng mL(-1), t(1/2) = 2.58 h). Moreover, molecular docking was further implemented to propose the preponderant configuration of compound 2e, providing important and useful guidelines for further development.
资助项目	National Natural Science Foundation of China[81673294] ; National Natural Science Foundation of China[81472862] ; National Natural Science Foundation of China[81425024]
WOS关键词	HUMAN INTERLEUKIN-8 RECEPTOR ; PANCREATIC-CANCER ; GROWTH ; IMMUNOTHERAPY ; ANGIOGENESIS ; POTENT ; CELLS
WOS研究方向	Chemistry
语种	英语
出版者	ROYAL SOC CHEMISTRY
WOS记录号	WOS:000429534200041
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272318]
专题	国家新药筛选中心药物化学研究室
通讯作者	Xie, Xin; Hu, Yong-Zhou
作者单位	1.Zhejiang Univ, Coll Pharmaceut Sci, ZJU ENS Joint Lab Med Chem, Hangzhou, Zhejiang, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, CAS Key Lab Receptor Res, Shanghai, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Laborarory Drug Res, Shanghai, Peoples R China;
推荐引用方式 GB/T 7714	Che, Jin-Xin,Wang, Zhi-Long,Dong, Xiao-Wu,et al. Bicyclo[2.2.1]heptane containing N,N-diarylsquaramide CXCR2 selective antagonists as anti-cancer metastasis agents[J]. RSC ADVANCES,2018,8(20):11061-11069.
APA	Che, Jin-Xin,Wang, Zhi-Long,Dong, Xiao-Wu,Hu, You-Hong,Xie, Xin,&Hu, Yong-Zhou.(2018).Bicyclo[2.2.1]heptane containing N,N-diarylsquaramide CXCR2 selective antagonists as anti-cancer metastasis agents.RSC ADVANCES,8(20),11061-11069.
MLA	Che, Jin-Xin,et al."Bicyclo[2.2.1]heptane containing N,N-diarylsquaramide CXCR2 selective antagonists as anti-cancer metastasis agents".RSC ADVANCES 8.20(2018):11061-11069.