Department of Chemistry, University of California, Davis, Davis, California 95616, USA.
Cancer Res. 2010 Jul 1;70(13):5448-56. doi: 10.1158/0008-5472.CAN-09-3736. Epub 2010 Jun 8.
Integrin alpha(4)beta(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 alpha(4)beta(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 alpha(4)beta(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.
整合素 α(4)β(1) 是一个有吸引力但研究不足的靶点，可用于选择性诊断和治疗 T 细胞和 B 细胞淋巴瘤。本报告重点介绍了与医学相关的苯并咪唑杂环作为整合素 α(4)β(1)拮抗剂的快速微波制备、构效关系和生物学评价。我们记录了用 (125)I 标记的衍生物在 B 细胞淋巴瘤异种移植鼠模型中的肿瘤摄取情况。整合素 α(4)β(1)的分子同源模型预测，对接的卤代苯并咪唑酰胺具有卤原子适合形成卤氢键的取向。鉴定出的高亲和力卤代配体为医学和生物学用途提供了有吸引力的工具，包括具有潜在放射性诊断 ((18)F) 或放射性治疗 ((131)I) 应用的氟代和碘代衍生物，或氯代和溴代类似物，可通过光亲和、交联/质谱和 X 射线晶体学研究提供对整合素-配体相互作用的结构见解。
