Cathepsin B inhibitors: Further exploration of the nitroxoline core.

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.

• Authors: Izidor Sosič, Ana Mitrović, Hrvoje Ćurić, Damijan Knez, Helena Brodnik Žugelj, Bogdan Štefane, Janko Kos, Stanislav Gobec
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 28 Issue 7 Pg. 1239-1247 (04 15 2018) ISSN: 1464-3405 [Electronic] England
• PMID: 29503024 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cysteine Proteinase Inhibitors
• Nitroquinolines
• nitroxoline
• CTSB protein, human
• Cathepsin B

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cathepsin B (antagonists & inhibitors, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cysteine Proteinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Humans
• Molecular Structure
• Nitroquinolines (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship