About this item:

26 Views | 0 Downloads

Author Notes:

Hyunsuk Shim, Department of Radiation Oncology, Emory University School of Medicine, 1701 Uppergate Drive, C5018, Atlanta, GA, USA, 30322., hshim@emory.edu.

Renren Bai, College of Pharmaceutical Sciences, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, Zhejiang, China, 310014., renrenbai@zjut.edu.cn; Department of Radiation Oncology, Emory University School of Medicine, 1701 Uppergate Drive, C5018, Atlanta, GA, USA, 30322., renren.bai@emory.edu.

Subjects:

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Chemistry, Medicinal
  • Pharmacology & Pharmacy
  • CXCR4
  • Hybrids
  • Amide-sulfamide
  • Inflammation
  • Inflammatory cell accumulation
  • CHEMOKINE RECEPTOR
  • SMALL-MOLECULE
  • ANTAGONISTS

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

Tools:

Journal Title:

European Journal of Medicinal Chemistry

Volume:

Volume 150

Publisher:

, Pages 195-205

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2018 Elsevier Masson SAS.All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Creative Commons License

Export to EndNote