Cathepsin B inhibitors: Further exploration of the nitroxoline core |
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Authors: | Izidor Sosič Ana Mitrović Hrvoje Ćurić Damijan Knez Helena Brodnik Žugelj Bogdan Štefane Janko Kos Stanislav Gobec |
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Institution: | 1. Faculty of Pharmacy, University of Ljubljana, A?ker?eva 7, 1000 Ljubljana, Slovenia;2. Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ve?na pot 113, 1000 Ljubljana, Slovenia;3. Department of Biotechnology, Jo?ef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia |
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Abstract: | Human cathepsin B is a cysteine protease with many house-keeping functions, such as intracellular proteolysis within lysosomes. Its increased activity and expression have been strongly associated with many pathological processes, including cancers. We present here the design and synthesis of novel derivatives of nitroxoline as inhibitors of cathepsin B. These were prepared either by omitting the pyridine part, or by modifying positions 2, 7, and 8 of nitroxoline. All compounds were evaluated for their ability to inhibit endopeptidase and exopeptidase activities of cathepsin B. For the most promising inhibitors, the ability to reduce extracellular and intracellular collagen IV degradation was determined, followed by their evaluation in cell-based in vitro models of tumor invasion. The presented data show that we have further defined the structural requirements for cathepsin B inhibition by nitroxoline derivatives and provided additional knowledge that could lead to non-peptidic compounds with usefulness against tumor progression. |
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Keywords: | Abz 2-aminobenzoyl AMC 7-amido-4-methylcoumarin catB cathepsin B DIPEA DMSO dimethyl sulfoxide ECM extracellular matrix EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HATU HOBt hydroxybenzotriazole inhibition constant TBTU Z benzyloxycarbonyl Human cathepsin B Nitroxoline derivatives Structure-activity relationships Tumor invasion |
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