Development of Fluorinated Peptoid-Based Histone Deacetylase (HDAC) Inhibitors for Therapy-Resistant Acute Leukemia

Abstract

Using a microwave-assisted protocol, we synthesized 16 peptoid-capped HDAC inhibitors (HDACi) with fluorinated linkers and identified two hit compounds. In biochemical and cellular assays, 10h stood out as a potent unselective HDACi with remarkable cytotoxic potential against different therapy-resistant leukemia cell lines. 10h demonstrated prominent antileukemic activity with low cytotoxic activity toward healthy cells. Moreover, 10h exhibited synergistic interactions with the DNA methyltransferase inhibitor decitabine in AML cell lines. The comparison of crystal structures of HDAC6 complexes with 10h and its nonfluorinated counterpart revealed a similar occupation of the L1 loop pocket but slight differences in zinc coordination. The substitution pattern of the acyl residue turned out to be crucial in terms of isoform selectivity. The introduction of an isopropyl group onto the phenyl ring provided the highly HDAC6-selective inhibitor 10p, which demonstrated moderate synergy with decitabine and exceeded the HDAC6 selectivity of tubastatin A.

Solid-Phase Parallel Synthesis of Dual Histone Deacetylase-Cyclooxygenase Inhibitors

“…This effect was more pronounced when a fluorine atom was introduced in meta -position to the hydroxamic acid ( A5 and B5 ). The beneficial effect of a fluorinated benzyl linker with regard to HDAC6 selectivity is in line with recent results disclosed by us and others [ 38 , 43 , 44 ]. Notably, the benzimidazole-fluorobenzyl-based compounds A6 (IC 50 HDAC1 = >2.80 µM; IC 50 HDAC6 = 0.011 µM; SI = >254) and B6 (IC 50 HDAC1 = 0.829 µM; IC 50 HDAC6 = 0.005 µM; SI = 166) demonstrated potent and highly selective HDAC6 inhibition, which is in excellent agreement with a recent report on HDAC6-selective proteolysis-targeting chimeras (PROTACs) [ 45 ]).…”

The Impact of Fluorination on the Design of Histone Deacetylase Inhibitors

“…In contrast, this is hindered in class I HDAC (e.g., HDAC1) because the Ser531 is exchanged by an Arg. These results of Sandrone et al [ 83 ] were similarly confirmed in the study of Reßing, Schliehe-Diecks et al, where an increased inhibition of HDAC4 (HDAC class IIa) was detected due to compounds with a fluorinated linker [ 84 ].…”

Difluoromethyl-1,3,4-oxadiazoles Are Selective, Mechanism-Based, and Essentially Irreversible Inhibitors of Histone Deacetylase 6

“…63 In vitro inhibitory activities against HDAC4 were measured using a previously published protocol with slight modifications. 67 For compounds and controls, threefold serial dilutions of the respective DMSO-stock solution in assay buffer (50 mM Tris−HCl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1.0 mM MgCl 2 •6 H 2 O, 5 mg/mL BSA) were prepared and 5.0 μL of this serial dilution was transferred into OptiPlate-96 black microplates (PerkinElmer). Then, 25 μL of assay buffer and 10 μL of enzyme solution (human recombinant HDAC1 (BPS Bioscience, Catalog no.…”