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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.
- Source :
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European Journal of Medicinal Chemistry . Oct2020, Vol. 204, pN.PAG-N.PAG. 1p. - Publication Year :
- 2020
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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- t hio u reido t hio p hene-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 (IC 50 = 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. Image 1 • TUTP compounds were identified as novel CXCR2 antagonists through scaffold-hopping strategy. • TUTP compounds are selective for CXCR2 among over 50 other GPCRs. • TUTP compounds inhibited CXCL8-mediated β-arrestin recruitment and the phosphorylation of ERK1/2. • Combination of TUTP compounds with doxorubicin showed synergistic cytotoxicity in human SKOV3 ovarian cancer cells. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 02235234
- Volume :
- 204
- Database :
- Academic Search Index
- Journal :
- European Journal of Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 145995330
- Full Text :
- https://doi.org/10.1016/j.ejmech.2020.112387