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Issue 20, 2018
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Bicyclo[2.2.1]heptane containing N,N′-diarylsquaramide CXCR2 selective antagonists as anti-cancer metastasis agents

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Abstract

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 (CXCR2IC50 = 48 nM) and good selectivity (CXCR1IC50/CXCR2IC50 = 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, Cmax = 2863 ng mL−1, t1/2 = 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.

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

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Supplementary files

Article information


Submitted
01 Mar 2018
Accepted
09 Mar 2018
First published
21 Mar 2018

This article is Open Access

RSC Adv., 2018,8, 11061-11069
Article type
Paper

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

J. Che, Z. Wang, X. Dong, Y. Hu, X. Xie and Y. Hu, RSC Adv., 2018, 8, 11061
DOI: 10.1039/C8RA01806E

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