Evaluation of functional groups on amino acids in cyclic tetrapeptides in histone deacetylase inhibition

Abstract

The naturally occurring cyclic tetrapeptide, chlamydocin, originally isolated from fungus Diheterospora chlamydosphoria, consists of α-aminoisobutyric acid, L-phenylalanine, D-proline and an unusual amino acid (S)-2-amino-8-((S)-oxiran-2-yl)-8-oxooctanoic acid (Aoe) and inhibits the histone deacetylases (HDACs), a class of regulatory enzymes. The epoxyketone moiety of Aoe is the key functional group for inhibition. The cyclic tetrapeptide scaffold is supposed to play important role for effective binding to the surface of enzymes. In place of the epoxyketone group, hydroxamic acid and sulfhydryl group have been applied to design inhibitor ligands to zinc atom in catalytic site of HDACs. In the research for more potent HDAC inhibitors, we replaced the epoxyketone moiety of Aoe with different functional groups and synthesized a series of chlamydocin analogs as HDAC inhibitors. Among the functional groups, methoxymethylketone moiety showed as potent inhibition as the hydroxamic acid. On the contrary, we confirmed that borate, trifruoromethylketone, and 2-aminoanilide are almost inactive in HDAC inhibition.

Natural and Synthetic Macrocyclic Inhibitors of the Histone Deacetylase Enzymes

“…For example, several of the apicidins ( 24 a , 24 b , and 24 e ) exhibit very potent HDAC inhibition in the nanomolar range although they contain a ketone or hydroxyketone, which are considered relatively weak Zn 2+ ‐binding groups . The majority of cyclic tetrapeptide HDAC inhibitors tested on enzyme isozyme level are selective towards class I, with no or low inhibitory activity against classes IIa and IIb . Potencies against HDAC1 (class I) and HDAC6 (class IIb), together with the HDAC activity in HeLa nuclear extract (N.E.…”

“…However, this has not been confirmed experimentally, to the best of our knowledge. The α‐epoxyketones represent some of the most potent cyclic tetrapeptide HDAC inhibitors in vitro . However, in vivo evaluation of chlamydocin in rats revealed low toxicity as well as low oncostatic effect, which was attributed to rapid inactivation as demonstrated by short half‐lives (<4 min) in both rabbit and rat blood in vitro …”

Synthesis and evaluation of N8-acetylspermidine analogues as inhibitors of bacterial acetylpolyamine amidohydrolase

“…However, each compound differs in the nature of its head group designed to mimic substrate or tetrahedral transition state binding to the active site Zn 2+ ion. Most of these Zn 2+ -binding groups have been successfully incorporated into effective inhibitors of HDACs 29, 33–39 and other metallohydrolases. 40–43 …”

“…59 In general, the incorporation of each of these functional groups in the design of HDAC inhibitors resulted in the generation of highly potent compounds with inhibitory potency in the nanomolar range. 33, 35–39 However, in contrast to our N 8 -acetylspermidine analogues, HDAC inhibitors are designed based on the combination of a metal-binding group, a linker, and an active site-capping group. For a given Zn 2+ -binding group, optimization of the linker and the capping group to optimize interactions with the mouth of the active site cleft is usually required to achieve exceptional inhibitory potency.…”

An efficient synthesis of SK-658 and its analogs as potent histone deacetylase inhibitors

“…The surface binding groups reported so far are aliphatic [3], aromatic [4], non-peptides [5], mono-peptides [6], cyclic tetrapeptides [7][8][9][10][11], bicyclic tetrapeptides [12,13] etc. and the zinc binding groups are, for instance, hydroxamic acid [14], retro-hydroxamic acid [11], o-aminoanilide, thioether [4], ketone, hydroxymethylketone, carbonyl [15], trifluoromethylketone [10], methoxymethylketone, azide, acrylamide, chloroacetamide, triazolyl [16], borate [17], mercaptan, carboxyl [18], phosphate [19] and so on. Now the burning question is to find out potent and isoform selective HDAC inhibitors to avoid various side effects.…”