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Author Notes:

Corresponding authors: Suazette Reid Mooring, Department of Chemistry, Georgia State University; phone, 404-413-5527; smooring@gsu.edu; address, 519A Science Annex, Atlanta, GA 30302-4098.

Hyunsuk Shim, Department of Radiology and Imaging Science, Emory University School of Medicine; phone, 404-778-4564; fax, 404-778-5550; hshim@emory.edu; address, 1365C Clifton Road, NE, C5008, Atlanta, GA 30322

We thank Ms. Jessica Paulishen and Mr. Andrew Teodorescu for proof-reading.

Subjects:

Research Funding:

This study was financially supported by a research grant from NIH NCI (R01 CA165306).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Chemistry, Medicinal
  • Pharmacology & Pharmacy
  • Tertiary amines
  • CXCR4 inhibitors
  • Binding affinity
  • Matrigel invasion
  • Anti-inflammatory activity
  • BREAST-CANCER METASTASIS
  • RECEPTOR 4 CXCR4
  • SMALL-MOLECULE
  • ANTIINFLAMMATORY DRUGS
  • CHEMOKINE RECEPTORS
  • ANTAGONISTS
  • DISCOVERY
  • MIGRATION
  • CYCLOOXYGENASE-2
  • THERAPEUTICS

Symmetrical bis-tertiary amines as novel CXCR4 inhibitors

Tools:

Journal Title:

European Journal of Medicinal Chemistry

Volume:

Volume 118

Publisher:

, Pages 340-350

Type of Work:

Article | Post-print: After Peer Review

Abstract:

CXCR4 inhibitors are promising agents for the treatment of cancer metastasis and inflammation. A series of novel tertiary amine derivatives targeting CXCR4 were designed, synthesized, and evaluated. The central benzene ring linker and side chains were modified and optimized to study the structure-activity relationship. Seven compounds displayed much more potent activity than the reference drug, AMD3100, in both the binding affinity assay and the blocking of Matrigel invasion functional assay. These compounds exhibited effective concentration ranging from 1 to 100 nM in the binding affinity assay and inhibited invasion from 65.3% to 100% compared to AMD3100 at 100 nM. Compound IIn showed a 50% suppressive effect against carrageenan-induced paw inflammation in a mouse model, which was as effective as the peptidic antagonist, TN14003 (48%). These data demonstrate that symmetrical bis-tertiary amines are unique CXCR4 inhibitors with high potency.

Copyright information:

© 2016 Elsevier Masson SAS. All rights reserved.

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