Non-Peptide Macrocyclic Histone Deacetylase Inhibitors

Abstract

Inhibition of Histone Deacetylases inhibitors (HDACi) hold great promise in cancer therapy due to their demonstrated ability to arrest proliferation of nearly all transformed cell types. Of the several structurally distinct small molecules HDACi reported, macrocyclic depsipeptides have the most complex recognition cap-group moieties and present an excellent opportunity for the modulation of the biological activities of HDACi. Unfortunately, the structure-activity relationship (SAR) studies for this class of compounds have been impaired largely because most macrocyclic HDACi known to date are comprised of complex peptide macrocycles. In addition to retaining the pharmacologically disadvantaged peptidyl-backbone, they offer only limited opportunity for side-chain modifications. Here we report the discovery of a new class of macrocyclic HDACi based on the macrolide antibiotics skeletons. SAR studies revealed that these compounds displayed both linker-length and macrolidetype dependent HDAC inhibition activities with IC 50 in low nanomolar range. In addition, these nonpeptide macrocyclic HDACi are more selective against HDAC 1 and 2 relative to HDAC 8, another class I HDAC isoform, hence have sub-class HDAC isoform selectivity.

Click Chemistry: 1,2,3‐Triazoles as Pharmacophores

“…Discovery of a new class of macrocyclic histone deacetylase inhibitors (HDACi) based on macrolide antibiotics skeletons (73) was reported by Oyelere et al [137] SAR studies revealed that these compounds displayed both linker-lengthand macrolide-type-dependent HDAC inhibition activities with IC 50 in the nanomolar range. These nonpeptide macrocyclic HDACi were also found to be more selective against HDACs 1 and 2 relative to HDAC 8.…”

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

“…However, the exact relationship between zinc chelation, protein acetylation state, and splicing inhibition is not clear, as only a limited set of HDAC inhibitors (HDACis) was screened. In the present work, we sought to clarify this relationship by screening a HDACi library that was structurally more diverse (Chen et al 2008;Canzoneri et al 2009;Oyelere et al 2009;Mwakwari et al 2010a,b;Patil et al 2010). We report here the elucidation of unique molecular features that confer splicing inhibition upon zinc-chelating agents with HDAC inhibition activity.…”

“…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.…”

Antibacterial Activity of Novel Sulfonylureas, Ureas and Thioureas of 15-Membered Azalides

“…Antibacterial macrolides have attracted considerable attention for two main reasons: (a) the emergence of atypical and/or new pathogens and extensive clinical application of these antibiotics had resulted in an increasing emergence of bacterial resistance, especially among macrolideresistant Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus strains, and, therefore, the development of alternative antibacterial agents became essential; (b) macrolide derivatives, especially 14-and 15-membered classes, have also become interesting for treating important chronic diseases, that is, asthma, chronic sinusitis, diffuse panbronchiolitis, cystic fibrosis (Čulić, 2001;Labro, 2000;Labro, 2004), bronchiolitis obliterans syndrome (BOS) (Vanaudenaerde et al, 2008;Culic et al, 2006), etc. Some macrolides proved active in treatment of malaria Kuschner et al, 1994;Andersen et al, 1995;Ohrt et al, 2002;Sidhu et al, 2007) and cancer (Romano et al, 2004;Oyelere et al 2009;Mwakwari et al 2010;Bao et al, 2010), showed antiparasitic activity (Lee et al 2011) or act as motilides, ie. macrolides with gastrointestinal motor stimulating activity (Takanashi et al 2009).…”