Design and synthesis of bioreductive prodrugs of class I histone deacetylase inhibitors and their biological evaluation in virally transfected acute myeloid leukemia cells

Although histone deacetylase (HDAC) inhibitors show promise in treating various types of hematologic malignancies, they have some limitations, including poor pharmacokinetics and off-target side effects, which may be a reason to exclude many of them from further drug development. Prodrug design has shown promise as an approach to improve pharmacokinetic properties and also to improve target tissue specificity. In the present work, several bioreductive prodrugs for class I HDACs were designed and synthesized based on known selective HDAC inhibitors. The zinc-binding group of the HDAC inhibitors was masked with various nitroarylmethyl residues to make them substrates of nitroreductase (NTR). The developed prodrugs showed very weak HDAC inhibitory activity compared to their parent inhibitors. The prodrugs were also tested against wild-type and NTR-transfected THP1 cells. Cellular assays showed that both 2-nitroimidazole-based prodrugs 5 and 6 were best activated by the NTR prodrug system and exhibited potent activity against NTR-THP1 cells. Compound 6 showed the highest cellular activity (GI50 = 77 nM) and also exhibited a moderate selectivity window. Moreover, activation of the prodrug by NTR was confirmed by LC-MS analysis, which showed the release of the parent inhibitor after incubation of prodrug 6 with E. coli NTR. Thus, compound 6 can be considered as a novel prodrug selective for class I HDACs with good bioreductive properties, which could be used as a good starting point for increasing selectivity and for further optimization.