Benzenesulfonamides: A Unique Class of Chemokine Receptor Type 4 Inhibitors

• Published in: ChemMedChem Vol. 8; no. 4; pp. 622 - 632
• Main Authors: Mooring, Suazette Reid, Liu, Jin, Liang, Zhongxing, Ahn, Jeffrey, Hong, Samuel, Yoon, Younghyoun, Snyder, James P., Shim, Hyunsuk
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.04.2013; WILEY‐VCH Verlag
• Subjects: Benzenesulfonamides; Binding Sites; Cell Line, Tumor; Chemokine CXCL12 - chemistry; Chemokine CXCL12 - metabolism; CXCR4 inhibitors; Drug Design; Humans; inflammation; metastasis; Molecular Docking Simulation; Protein Binding; Protein Interaction Maps; Protein Structure, Tertiary; Pyridines - chemistry; Receptors, CXCR4 - antagonists & inhibitors; Receptors, CXCR4 - metabolism; sulfonamides; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - metabolism
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201200582

The interaction of CXCR4 with CXCL12 (SDF‐1) plays a critical role in cancer metastasis by facilitating the homing of tumor cells to metastatic sites. Based on our previously published work on CXCR4 antagonists, we have synthesized a series of aryl sulfonamides that inhibit the CXCR4/CXCL12 interaction. Analogue bioactivities were assessed with binding affinity and Matrigel invasion assays. Computer modeling was employed to evaluate a selection of the new analogues docked into the CXCR4 X‐ray structure and to rationalize discrepancies between the affinity and Matrigel in vitro assays. A lead compound displays nanomolar potency in the binding affinity assay (IC50=8.0 nM) and the Matrigel invasion assay (100 % blockade of invasion at 10 nM). These data demonstrate that benzenesulfonamides are a unique class of CXCR4 inhibitors with high potency. Running interference: A series of sulfonamide analogues were synthesized by modification of the tunable area around the previously synthesized potent dipyridine 1. Several of these analogues inhibit the CXCR4–CXCL12 interaction, and are suitable leads for the development of anti‐metastasis agents.