Non-Peptide Macrocyclic Histone Deacetylase Inhibitors Derived from Tricyclic Ketolide Skeleton

Abstract

Inhibition of histone deacetylase (HDAC) function is a validated therapeutic strategy for cancer treatment. Of the several structurally distinct small molecule histone deacetylase inhibitors (HDACi) reported, macrocyclic depsipeptides possess the most complex cap-groups and have demonstrated excellent HDAC inhibition potency and isoform selectivity. Unfortunately, the development of macrocyclic depsipeptides has been hampered in part due to development problems characteristic of large peptides and the complex reaction schemes required for their synthesis. Herein we report that tricyclic ketolide TE-802 is an excellent mimetic for the peptide backbone of macrocyclic HDACi. Compounds derived from this template are particularly selective against HDAC 1 and 2 with nanomolar inhibitory activity. Interrogation of the association between a subset of these compounds and key HDAC isoforms, using AutoDock, enables a molecular description of the interaction between the HDAC enzyme's outer rim and the inhibitors' macrocyclic cap group that are responsible for compound affinity and presumably isoform selectivity.

Molecular architecture of zinc chelating small molecules that inhibit spliceosome assembly at an early stage

“…To this end, we first screened a small (63-member), yet structurally diverse HDACi library (see Supplemental Table S1 for the structures) at 100 mM using a conventional in vitro splicing assay. The HDAC inhibition activity of compounds in the screened library against HDAC1 and HeLa cell nuclear extract HDACs ranges from single digit-to mid-nanomolar (Chen et al 2008;Canzoneri et al 2009;Oyelere et al 2009;Mwakwari et al 2010a;Patil et al 2010). Despite their potency, these HDACis did not broadly inhibit splicing.…”

“…In vitro HDAC inhibition was assayed using the HDAC Fluorimetric Assay/Drug Discovery Kit as previously described (Chen et al 2008;Oyelere et al 2009;Mwakwari et al 2010a). Briefly, 15 mL of HeLa nuclear extract was mixed with 5 mL of 103 compound and 5 mL of assay buffer.…”

Cap-Modified Hydroxamate Analogues as Histone Deacetylases Inhibitors and Antitumor Agents

“…In vitro HDAC inhibition was assayed using the HDAC Fluorimetric Assay/Drug Discovery Kit as previously described. 21 Briefly, 15 L of HeLa nuclear extract was mixed with three concentrations of compound sample and 5 L of assay buffer. Fluorogenic substrate (25 L) was added, and reaction was allowed to proceed for 15 min at room temperature and then stopped by addition of a developer containing TSA.…”

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

“…Targeting surface recognition group modification and zinc binding group optimization, a large number of structurally diverse HDAC inhibitors have been reported in the literatures and patented as the possible candidates for cancer drug. 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.…”