Synthesis and evaluation of near-infrared fluorescent sulfonamide derivatives for imaging of hypoxia-induced carbonic anhydrase IX expression in tumors
| Autor: | Wael Yared, Kevin Groves, Garry Cuneo, Bagna Bao, Jeffrey D. Peterson, Paul Kennedy, Claudiu T. Supuran, Emma Handy, Milind Rajopadhye, Jun Zhang |
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| Rok vydání: | 2012 |
| Předmět: |
Clinical Biochemistry
Pharmaceutical Science Biochemistry Gene Expression Regulation Enzymologic HeLa Mice Cytosol Antigens Neoplasm In vivo Cell Line Tumor Neoplasms Carbonic anhydrase Drug Discovery medicine Fluorescence microscope Animals Humans Carbonic Anhydrase IX Hypoxia Molecular Biology Carbonic Anhydrases Fluorescent Dyes Sulfonamides Dose-Response Relationship Drug biology Chemistry Organic Chemistry biology.organism_classification In vitro Up-Regulation Kinetics Microscopy Fluorescence Models Chemical Cell culture Drug Design biology.protein Molecular Medicine Tomography X-Ray Computed Acetazolamide Neoplasm Transplantation Ex vivo HeLa Cells medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 22:653-657 |
| ISSN: | 0960-894X |
| Popis: | A series of human carbonic anhydrase (hCA) IX inhibitors conjugated to various near-infrared fluorescent dyes was synthesized with the aim of imaging hypoxia-induced hCA IX expression in tumor cells in vitro, ex vivo and in vivo. The resulting compounds were profiled for inhibition of transmembrane hCA IX showing a range of potencies from 7.5 to 116 nM and up to 50-fold selectivity over the cytosolic form hCA II. Some of the compounds also showed inhibition selectivity for other transmembrane forms hCA XII and XIV as well. Compounds incubated in vitro with HeLa cells cultured under normoxic and hypoxic conditions detected upregulation of hCA IX under hypoxia by fluorescence microscopy. A pilot in vivo study in HT-29 tumor bearing mice showed significant accumulation of a fluorescent acetazolamide derivative in tumor tissue with little accumulation in other tissues. Approximately 10% of injected dose was non-invasively quantified in tumors by fluorescence molecular tomography (FMT), demonstrating the promise of these new compounds for quantitative imaging of hCA IX upregulation in live animals. |
| Databáze: | OpenAIRE |
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