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The Design, Synthesis, and Evaluation of Hypoxia-Activated Prodrugs of the KDAC Inhibitor Panobinostat

preprint
submitted on 30.12.2020, 12:59 and posted on 31.12.2020, 07:56 by Ewen Calder, Anna Skwarska, Deborah Sneddon, Lisa Folkes, Ishna N. Mistry, Ester M. Hammond, Stuart Conway
The design and synthesis of four hypoxia-activated prodrugs of the KDAC inhibitor panobinostat is described. Initial validation of these compounds using isolated enzymes, and in two human cancer cell lines, reveals that the nitroimidazole-based prodrug (NI-Pano, CH-03) undergoes efficient bioreduction and fragmentation to release the parent drug, panobinostat. NI-Pano was identified as the optimum compound for use in further studies in cells, spheroid tumor models, and in vivo.

Funding

Chemical bioreductive approaches to targeted radiosensitisation and imaging of tumours

Medical Research Council

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Chemical biology tools for investigating the chemistry of cellular REDOX stress

Engineering and Physical Sciences Research Council

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History

Email Address of Submitting Author

stuart.conway@chem.ox.ac.uk

Institution

University of Oxford

Country

UK

ORCID For Submitting Author

0000-0002-5148-117X

Declaration of Conflict of Interest

None.

Version Notes

Version 1.

Exports