Anti-inflammatory hybrids of secondary amines and amide-sulfamide derivatives

• Type of Material: Article
• Authors: Renren Bai, Zhejiang University of Technology; Jian Sun, Zhejiang University of Technology; Zhongxing Liang, Emory University; Younghyoun Yoon, Emory University; Eric Salgado, Emory University; Amber Feng, Emory University; Yoonhyeun Oum, Emory University; Yuanyuan Xie, Zhejiang University of Technology; Hyunsuk Shim, Emory University
• Language: English
• Date: 2018-04-25
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Elsevier Masson SAS.All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.ejmech.2018.02.085
• Title of Journal or Parent Work: European Journal of Medicinal Chemistry
• ISSN: 0223-5234
• Volume: 150
• Start Page: 195
• End Page: 205
• Keywords: Amide-sulfamide; Hybrids; CHEMOKINE RECEPTOR; CXCR4; ANTAGONISTS; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; Inflammatory cell accumulation; Inflammation; Chemistry, Medicinal; SMALL-MOLECULE
• Research Categories: Chemistry, Pharmaceutical; Health Sciences, Oncology; Health Sciences, Radiology

Abstract

The CXCR4/CXCL12 chemokine axis can chemotactically accumulate inflammatory cells to local tissues and regulate the release of inflammatory factors. Developing novel CXCR4 modulators may provide a desirable strategy to control the development of inflammation. A series of novel hybrids were designed by integrating the key pharmacophores of three CXCR4 modulators. The majority of compounds displayed potent CXCR4 binding affinity. Compound 7a exhibited 1000-fold greater affinity than AMD3100 and significantly inhibited invasion of CXCR4-positive tumor cells. Additionally, compound 7a blocked mice ear inflammation by 67% and suppressed the accumulation of inflammatory cells in an in vivo mouse ear edema evaluation. Western blot analyses revealed that 7a inhibited the CXCR4/CXCL12-mediated phosphorylation of Akt and p44 in a dose-dependent manner. Moreover, compound 7a had no observable cytotoxicity and displayed a favorable plasma stability in our preliminary pharmacokinetic study. These results confirmed that this is a feasible method to develop CXCR4 modulators for the regulation and reduction of inflammation.