Efficient Palladium-Triggered Release of Vorinostat from a Bioorthogonal Precursor

• Published in: Journal of medicinal chemistry Vol. 59; no. 21; pp. 9974 - 9980
• Main Authors: Rubio-Ruiz, Belén, Weiss, Jason T, Unciti-Broceta, Asier
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.11.2016; Amer Chemical Soc
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Catalysis; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemistry, Medicinal; Dose-Response Relationship, Drug; Drug Liberation - drug effects; Drug Screening Assays, Antitumor; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - metabolism; Humans; Hydroxamic Acids - chemistry; Hydroxamic Acids - pharmacology; Life Sciences & Biomedicine; Molecular Structure; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Palladium - chemistry; Palladium - pharmacology; Pharmacology & Pharmacy; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacology; Science & Technology; Structure-Activity Relationship; Tumor Cells, Cultured; CATALYSIS; SAHA; CYCLOADDITION; ACTIVATION; PRODRUG; SUBEROYLANILIDE HYDROXAMIC ACID; MEDIATED DEALKYLATION; CHEMISTRY; HISTONE DEACETYLASE INHIBITORS; LIVING CELLS
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b01426

Bioorthogonal uncaging strategies have recently emerged as an experimental therapeutic approach to control drug release. Herein we report a novel masking strategy that enables to modulate the metal chelating properties of hydroxamic acid groups by bioorthogonal chemistry using Pd-functionalized resins. This novel approach allowed to devise an inactive precursor of the histone deacetylase inhibitor vorinostat that was efficiently uncaged by heterogeneous Pd catalysis in cell culture models of glioma and lung cancer.