Palladium-catalyzed cross-coupling reactions on a bromo-naphthalene scaffold in the search for novel human CC chemokine receptor 8 (CCR8) antagonists

Yenthel Verhaegen; Libao Liu; Tien T Nguyen; Tom Van Loy; Arnout R D Voet; Dominique Schols; Wim Dehaen; Steven De Jonghe

doi:10.1016/j.bioorg.2020.104560

Palladium-catalyzed cross-coupling reactions on a bromo-naphthalene scaffold in the search for novel human CC chemokine receptor 8 (CCR8) antagonists

Bioorg Chem. 2021 Feb:107:104560. doi: 10.1016/j.bioorg.2020.104560. Epub 2020 Dec 16.

Authors

Yenthel Verhaegen¹, Libao Liu², Tien T Nguyen³, Tom Van Loy², Arnout R D Voet³, Dominique Schols², Wim Dehaen¹, Steven De Jonghe⁴

Affiliations

¹ KU Leuven, Department of Chemistry, Molecular Design and Synthesis, Celestijnenlaan 200F, box 2404, 3001 Leuven, Belgium.
² KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49, box 1043, 3000 Leuven, Belgium.
³ KU Leuven, Department of Chemistry, Biochemistry, Molecular and Structural Biology, Celestijnenlaan 200G, box 2403, 3001 Leuven, Belgium.
⁴ KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49, box 1043, 3000 Leuven, Belgium. Electronic address: steven.dejonghe@kuleuven.be.

PMID: 33383325
DOI: 10.1016/j.bioorg.2020.104560

Abstract

The naphthalene sulfonamide scaffold is known to possess CCR8 antagonistic properties. In order to expand the structure-activity relationship study of this compound class, a variety of palladium-catalyzed cross-coupling reactions was performed on a bromo-naphthalene precursor yielding a diverse library. These compounds displayed CCR8 antagonistic properties in binding and calcium mobilization assays, with IC₅₀ values in the 0.2 - 10 µM range. The decreased activity, when compared to the original lead compound, was rationalized by homology molecular modeling.

Keywords: Antagonist; CCR8; GPCR; Naphthalene sulfonamide.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Bromine / chemistry*
Catalysis
Humans
Molecular Docking Simulation
Naphthalenes / chemistry*
Naphthalenes / metabolism
Palladium / chemistry*
Protein Binding
Protein Structure, Tertiary
Receptors, CCR8 / antagonists & inhibitors*
Receptors, CCR8 / metabolism
Structure-Activity Relationship

Substances

CCR8 protein, human
Naphthalenes
Receptors, CCR8
Palladium
Bromine