RESUMEN
A novel synthesis of the naturally occurring HDAC inhibitor WF-3161 is described. Key steps include the Matteson homologation to generate the stereogenic centres in the side chain, and Pd-catalysed C-H functionalisation to connect the side chain to the peptide backbone. WF-3161 was found to be highly selective for HDAC1, whereas no activity was observed towards HDAC6. High activity was also found against the cancer cell line HL-60.
Asunto(s)
Inhibidores de Histona Desacetilasas , Histona Desacetilasas , Inhibidores de Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Histona Desacetilasa 6 , PéptidosRESUMEN
Anticancer drug conjugates are an emerging approach for future cancer treatment. Here, we report a series of hybrid ligands merging the neurohormone melatonin with the approved histone deacetylase (HDAC) inhibitor vorinostat, using melatonin's amide side chain (3a-e), its indolic nitrogen (5a-d), and its ether oxygen (7a-d) as attachment points. Several hybrid ligands showed higher potency thanvorinostat in both HDAC inhibition and cellular assays on different cultured cancer cell lines. In the most potent HDAC1 and HDAC6 inhibitors, 3e, 5c, and 7c, the hydroxamic acid moiety of vorinostat is linked to melatonin through a hexamethylene spacer. Hybrid ligands 5c and 7c were also found to be potent growth inhibitors of MCF-7, PC-3M-Luc, and HL-60 cancer cell lines. As these compounds showed only weak agonist activity at melatonin MT1 receptors, the findings indicate that their anticancer actions are driven by HDAC inhibition.
Asunto(s)
Antineoplásicos , Melatonina , Neoplasias , Vorinostat/farmacología , Histona Desacetilasas/metabolismo , Histona Desacetilasas/farmacología , Melatonina/farmacología , Ligandos , Relación Estructura-Actividad , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/química , Antineoplásicos/farmacología , Antineoplásicos/química , Ácidos Hidroxámicos/farmacología , Línea Celular Tumoral , Proliferación Celular , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 1/farmacología , Histona Desacetilasa 6RESUMEN
Dysregulation of both tubulin deacetylases sirtuin 2 (Sirt2) and the histone deacetylase 6 (HDAC6) has been associated with the pathogenesis of cancer and neurodegeneration, thus making these two enzymes promising targets for pharmaceutical intervention. Herein, we report the design, synthesis, and biological characterization of the first-in-class dual Sirt2/HDAC6 inhibitors as molecular tools for dual inhibition of tubulin deacetylation. Using biochemical in vitro assays and cell-based methods for target engagement, we identified Mz325 (33) as a potent and selective inhibitor of both target enzymes. Inhibition of both targets was further confirmed by X-ray crystal structures of Sirt2 and HDAC6 in complex with building blocks of 33. In ovarian cancer cells, 33 evoked enhanced effects on cell viability compared to single or combination treatment with the unconjugated Sirt2 and HDAC6 inhibitors. Thus, our dual Sirt2/HDAC6 inhibitors are important new tools to study the consequences and the therapeutic potential of dual inhibition of tubulin deacetylation.