Abstract
We report the synthesis and evaluation of a class of selective multitarget agents for the inhibition of HDAC6, HDAC8, and HDAC10. The concept for this study grew out of a structural analysis of the two selective inhibitors Tubastatin A (HDAC6/10) and PCI‐34051 (HDAC8), which we recognized share the same N‐benzylindole core. Hybridization of the two inhibitor structures resulted in dihydroxamic acids with benzyl‐indole and ‐indazole core motifs. These substances exhibit potent activity against HDAC6, HDAC8, and HDAC10, while retaining selectivity over HDAC1, HDAC2, and HDAC3. The best substance inhibited the viability of the SK‐N‐BE(2)C neuroblastoma cell line with an IC50 value similar to a combination treatment with Tubastatin A and PCI‐34051. This compound class establishes a proof of concept for such hybrid molecules and could serve as a starting point for the further development of enhanced HDAC6/8/10 inhibitors.
Highlights
We recently showed that Tubastatin A, which is annotated as a selective HDAC6 inhibitor, is a highly potent HDAC10 binder.[19]
We have previously demonstrated that a basic nitrogen in the cap group of Tubastatin A analogs is important for potent
As our primary interest was to target HDAC8 and HDAC10, the substances were first tested against the two proteins in an enzymatic (HDAC-GloTM I/II) and a ligand displacement FRET
Summary
In PCI-34051 (Figure 1, top left) the indole moiety (blue) functions as the linker with a ZBG at C6, it is part of the γcarboline cap group (orange) of Tubastatin A (Figure 1, top right). The hydroxamic acid on the heterocycle would serve as the ZBG with respect to HDAC8 inhibition (Figure 1, lower left), with the phenyl hydroxamate functioning as part of the cap group. 2b and 3b were obtained from formylindoles 9 and 10, respectively, via reductive amination with dimethylamine to give 11 and 12, followed by hydroxamic acid formation.[25] The γ-carboline scaffold of Tubastatin A analogues 2c and 3c was prepared by Fischer indole synthesis using hydrazine 13 and 1methylpiperidin-4-one (14), with subsequent BOC protection to give 15 (Scheme 1, bottom). NH2OH (50 wt% in H2O), KCN or KOH, 1,4-dioxane, RT, 24–48 h, 11–72 %; c) HNMe2, CH2O, HOAc, MeOH/H2O (5 : 1), 0 to 70° C, 48 h, 46 %; d) 4carbomethoxybenzyl bromide or PMBCl, K2CO3, DMF, RT, 12–16 h, 85 % (9), 74 % (10); e) HNMe2, NaBH(OAc), MeOH/H2O, 0 °C to RT, 48 h, 50 % (11), 39 % (12); f) H2SO4, 1,4-dioxane, 60 °C, 20 h, 94 %; g) Boc2O, DMAP, CH2Cl2, RT, 15 min, 71 %; h) t-BuLi, N-formylmorpholine, THF, 100 °C, 10 min, 76 %; i) NaCN, MnO2, HOAc, MeOH, RT, 2 h, 73 %; j) TFA, CH2Cl2, 0 °C to RT, 2 h, 96 %; PMBCl, 4-methoxybenzyl chloride; Boc2O, di-t-butyl dicarbonate; DMAP, 4dimethylaminopyridine
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