Bioorthogonal Uncaging of the Active Metabolite of Irinotecan by Palladium-Functionalized Microdevices.

Autor: Adam C; Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, UK., Pérez-López AM; Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, UK., Hamilton L; Centre for Neurogeneration, The Chancellor's Building, University of Edinburgh, UK., Rubio-Ruiz B; Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, UK., Bray TL; Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, UK., Sieger D; Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, UK.; Centre for Neurogeneration, The Chancellor's Building, University of Edinburgh, UK., Brennan PM; Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, UK.; Centre for Clinical Brain Sciences, University of Edinburgh, UK., Unciti-Broceta A; Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, UK.
Jazyk: angličtina
Zdroj: Chemistry (Weinheim an der Bergstrasse, Germany) [Chemistry] 2018 Nov 13; Vol. 24 (63), pp. 16783-16790. Date of Electronic Publication: 2018 Nov 08.
DOI: 10.1002/chem.201803725
Abstrakt: SN-38, the active metabolite of irinotecan, is released upon liver hydrolysis to mediate potent antitumor activity. Systemic exposure to SN-38, however, also leads to serious side effects. To reduce systemic toxicity by controlling where and when SN-38 is generated, a new prodrug was specifically designed to be metabolically stable and undergo rapid palladium-mediated activation. Blocking the phenolic OH of SN-38 with a 2,6-bis(propargyloxy)benzyl group led to significant reduction of cytotoxic activity (up to 44-fold). Anticancer properties were swiftly restored in the presence of heterogeneous palladium (Pd) catalysts to kill colorectal cancer and glioma cells, proving the efficacy of this novel masking strategy for aromatic hydroxyls. Combination with a Pd-activated 5FU prodrug augmented the antiproliferative potency of the treatment, while displaying no activity in the absence of the Pd source, which illustrates the benefit of achieving controlled release of multiple approved therapeutics-sequentially or simultaneously-by the same bioorthogonal catalyst to increase anticancer activity.
(© 2018 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)
Databáze: MEDLINE
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