Azetidinones as Zinc‐Binding Groups to Design Selective HDAC8 Inhibitors

Abstract

2-Azetidinones, commonly known as beta-lactams, are well-known heterocyclic compounds. Herein we described the synthesis and biological evaluation of a series of novel beta-lactams. In vitro inhibition assays against HDAC isoforms showed an interesting isoform-selectivity of these compounds towards HDAC6 and HDAC8. The isoform selectivity changed in response to modification of the azetidinone-ring nitrogen atom substituent. The presence of an N-thiomethyl group is a prerequisite for the activity of these compounds in the micromolar range towards HDAC8.

HDAC8: a multifaceted target for therapeutic interventions

“…It exhibited limited cellular activity in T cell leukemia cells and no activity in other tumor cells [23,79] ( Figure 4A). Other chemical classes include the azetidinone 8, the cyclic thiourea SB-379278A (9), and the amino acid derivative 10 [80][81][82]. Compounds 1, 8, and 9 show moderate HDAC8 selectivity (not tested for all HDAC isoforms) and inhibitory activity within the micromolar range ( Table 1).…”

Synthesis and Biological Evaluation of ortho‐Aryl N‐Hydroxycinnamides as Potent Histone Deacetylase (HDAC) 8 Isoform‐Selective Inhibitors

“…[17] To date, several HDAC8 selective inhibitors have been reported. These include aryl hydroxamate (1), [21] azetidinone (2), [22] the pyridine-based thiourea SB-379278A, [23] the 12-membered macrocycle-based phenyl hydroxamate A8B4, [24] and indolebased PCI34051 [17] (Figure 1). Of these, compounds 1, 2, and SB-379278A had moderate HDAC8specific inhibitory activity within micromolar range.…”

Towards Selective Inhibition of Histone Deacetylase Isoforms: What Has Been Achieved, Where We Are and What Will Be Next

“…[115] For example, N-thiomethyl-azetidin-2-one 10 ( Figure 7) exhibits an IC 50 value of 9.56 mm against HDAC8 and > 1000 mm against HDAC6. [115] For example, N-thiomethyl-azetidin-2-one 10 ( Figure 7) exhibits an IC 50 value of 9.56 mm against HDAC8 and > 1000 mm against HDAC6.…”

“…Several monocyclic azetidinone derivatives were found to selectively inhibit HDAC8. [115] For example, N-thiomethyl-azetidin-2-one 10 (Figure 7) exhibits an IC 50 value of 9.56 mm against HDAC8 and > 1000 mm against HDAC6.…”