Design, Multicomponent Synthesis, and Anticancer Activity of a Focused Histone Deacetylase (HDAC) Inhibitor Library with Peptoid-Based Cap Groups
Abstract
In this work, we report the multicomponent synthesis of a focused histone deacetylase (HDAC) inhibitor library with peptoid-based cap groups and different zinc-binding groups. All synthesized compounds were tested in a cellular HDAC inhibition assay and an MTT assay for cytotoxicity. On the basis of their noteworthy activity in the cellular HDAC assays, four compounds were further screened for their inhibitory activity against recombinant HDAC1-3, HDAC6, and HDAC8. All four compounds showed potent inhibition of HDAC1-3 as well as significant inhibition of HDAC6 with IC50 values in the submicromolar concentration range. Compound 4j, the most potent HDAC inhibitor in the cellular HDAC assay, revealed remarkable chemosensitizing properties and enhanced the cisplatin sensitivity of the cisplatin-resistant head-neck cancer cell line Cal27CisR by almost 7-fold. Furthermore, 4j almost completely reversed the cisplatin resistance in Cal27CisR. This effect is related to a synergistic induction of apoptosis as seen in the combination of 4j with cisplatin.
Keywords
Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology
Cell Line
Tumor
Cell Proliferation/drug effects
Dose-Response Relationship
Drug
*Drug Design
Drug Screening Assays
Antitumor
Histone Deacetylase Inhibitors/chemical synthesis/chemistry/*pharmacology
Histone Deacetylases/*metabolism
Humans
Models
Molecular
Molecular Structure
Peptoids/chemical synthesis/chemistry/*pharmacology
Small Molecule Libraries/chemical synthesis/chemistry/*pharmacology
Structure-Activity Relationship