Halogenated Benzimidazole Carboxamides Target Integrin α4β1 on T-Cell and B-Cell Lymphomas

Integrin α 4 β 1 is an attractive but poorly understood target for selective diagnosis and treatment of T-cell and B-cell lymphomas. This report focuses on the rapid microwave preparation, structure-activity relationships, and biological evaluation of medicinally pertinent benzimidazole heterocycles as integrin α 4 β 1 antagonists. We documented tumor uptake of derivatives labeled with 125 I in xenograft murine models of B-cell lymphoma. Molecular homology models of integrin α 4 β 1 predicted that docked halobenzimidazole carboxamides have the halogen atom in a suitable orientation for halogen-hydrogen bonding. The high-affinity halogenated ligands identified offer attractive tools for medicinal and biological use, including fluoro and iodo derivatives with potential radiodiagnostic ( 18 F) or radiotherapeutic ( 131 I) applications, or chloro and bromo analogues that could provide structural insights into integrin-ligand interactions through photoaffinity, cross-linking/mass spectroscopy, and X-ray crystallographic studies. Cancer Res; 70(13); 5448–56. ©2010 AACR.