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Discovery, structure-activity relationship study and biological evaluation of 2-thioureidothiophene-3-carboxylates as a novel class of C-X-C chemokine receptor 2 (CXCR2) antagonists.

Abstract
The C-X-C motif ligand 8 and C-X-C chemokine receptor 2 (CXCL8-CXCR2) axis is involved in pathogenesis of various diseases including inflammation and cancers. Various CXCR2 antagonists are under development for several diseases. Our previous high-throughput cell-based assay specific for CXCR2 has identified a pyrimidine-based compound CX797 acting on CXCR2 down-stream signaling. A lead optimization campaign through scaffold-hopping strategy led to a series of 2-thioureidothiophene-3-carboxylates (TUTP) as novel CXCR2 antagonists. Structure-activity relationship study of TUTPs led to the identification of compound 52 that significantly inhibited CXCR2-mediated β-arrestin recruitment signaling (IC50 = 1.1±0.01 μM) with negligible effect on CXCL8-mediated cAMP signaling and calcium flux. Similar to the known CXCR2 antagonist SB265610, compound 52 inhibited CXCL8-CXCR2 induced phosphorylation of ERK1/2. TUTP compounds also inhibited CXCL8-mediated cell migration and showed synergy with doxorubicin in ovarian cancer cells, thereby supporting TUTPs as promising compounds for cancer treatment.
AuthorsDing Xue, Wenmin Chen, Nouri Neamati
JournalEuropean journal of medicinal chemistry (Eur J Med Chem) Vol. 204 Pg. 112387 (Oct 15 2020) ISSN: 1768-3254 [Electronic] France
PMID32829163 (Publication Type: Journal Article)
CopyrightCopyright © 2020 Elsevier Masson SAS. All rights reserved.
Chemical References
  • Carboxylic Acids
  • Receptors, Interleukin-8B
  • Thiophenes
  • beta-Arrestin 2
  • Doxorubicin
  • Cyclic AMP
Topics
  • Carboxylic Acids (chemistry, pharmacology)
  • Cell Line, Tumor
  • Cell Movement (drug effects)
  • Cyclic AMP (metabolism)
  • Doxorubicin (pharmacology)
  • Drug Design
  • Drug Synergism
  • Humans
  • Inhibitory Concentration 50
  • Phosphorylation (drug effects)
  • Receptors, Interleukin-8B (antagonists & inhibitors, metabolism)
  • Signal Transduction (drug effects)
  • Structure-Activity Relationship
  • Thiophenes (chemistry)
  • beta-Arrestin 2 (metabolism)

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