Synthesis and evaluation of squaramide and thiosquaramide inhibitors of the DNA repair enzyme SNM1A
| Autor: | Eva-Maria Dürr, Joanna F. McGouran, William Doherty, Mark Berney, Manav T Manoj, Werner Theodor Jauslin |
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| Rok vydání: | 2021 |
| Předmět: |
Membrane permeability
DNA repair Clinical Biochemistry Pharmaceutical Science Biochemistry Article Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Humans Nucleoside Enzyme Inhibitors Molecular Biology ComputingMethodologies_COMPUTERGRAPHICS chemistry.chemical_classification Nuclease Dose-Response Relationship Drug Molecular Structure Quinine biology Interstrand crosslink repair Organic Chemistry Squaramide Nuclease inhibitor DNA Repair Enzymes Enzyme chemistry biology.protein Molecular Medicine Zinc-binding group Thymidine SNM1A Thiosquaramide DNA |
| Zdroj: | Bioorganic & Medicinal Chemistry |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2021.116369 |
| Popis: | Graphical abstract SNM1A is a zinc-dependent nuclease involved in the removal of interstrand crosslink lesions from DNA. Inhibition of interstrand crosslink repair enzymes such as SNM1A is a promising strategy for improving the efficacy of crosslinking chemotherapy drugs. Initial studies have demonstrated the feasibility of developing SNM1A inhibitors, but the full potential of this enzyme as a drug target has yet to be explored. Herein, the synthesis of a family of squaramide- and thiosquaramide-bearing nucleoside derivatives and their evaluation as SNM1A inhibitors is reported. A gel electrophoresis assay was used to identify nucleoside derivatives bearing an N-hydroxysquaramide or squaric acid moiety at the 3′-position, and a thymidine derivative bearing a 5′-thiosquaramide, as candidate SNM1A inhibitors. Quantitative IC50 determination showed that a thymidine derivative bearing a 5′-thiosquaramide was the most potent inhibitor, followed by a thymidine derivative bearing a 3′-squaric acid. UV–Vis titrations were carried out to evaluate the binding of the (thio)squaramides to zinc ions, allowing the order of inhibitory potency to be rationalised. The membrane permeability of the active inhibitors was investigated, with several compounds showing promise for future in vivo applications. |
| Databáze: | OpenAIRE |
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