Melatonin-vorinostat hybrid ligands show higher histone deacetylase and cancer cell growth inhibition than vorinostat

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.

Automated summary

Anticancer drug conjugates that merge melatonin with the HDAC inhibitor vorinostat have shown higher potency in inhibiting HDAC and suppressing cancer cell growth. The most effective inhibitors, 3e, 5c, and 7c, linked the hydroxamic acid group of vorinostat to melatonin through a hexamethylene spacer. These hybrid ligands also demonstrated strong growth inhibition on various cancer cell lines. Their anticancer actions are driven by HDAC inhibition rather than melatonin receptor activation.