Alkyl-Substituted Polyaminohydroxamic Acids:  A Novel Class of Targeted Histone Deacetylase Inhibitors

Abstract

The reversible acetylation of histones is critical for regulation of eukaryotic gene expression. The histone deacetylase inhibitors trichostatin (TSA, 1), MS-275 (2) and suberoylanilide hydroxamic acid (SAHA, 3) arrest growth in transformed cells and in human tumor xenografts. However, 1-3 suffer from lack of specificity among the various HDAC isoforms, prompting us to design and synthesize polyaminohydroxamic acid (PAHA) derivatives 6-21. We felt that PAHAs would be selectively directed to chromatin and associated histones by the positively charged polyamine side chain. At 1 microM, compounds 12, 15 and 20 inhibited HDAC by 74.86, 59.99 and 73.85%, respectively. Although 20 was a less potent HDAC inhibitor than 1, it was more potent than 2, more effective as an initiator of histone hyperacetylation, and significantly more effective than 2 at re-expressing p21Waf1 in ML-1 leukemia cells. On the basis of these results, PAHAs 6-21 represent an important new chemical class of HDAC inhibitors.

Histone 3.3 Participates in a Self-Sustaining Cascade of Apoptosis That Contributes to the Progression of Chronic Obstructive Pulmonary Disease

“…We also found a previously unreported C-terminal acetylation at Lys 116 ( Figure 5; see Tables E4 and Table E5 and Figure E8). We confirmed the effect of acetylation on proteasome degradation, using histones that were purified from A549 cells treated with a combination of HDAC inhibitors (trichostatin, MS-275, and suberoylanilide hydroxamic acid) to produce hyperacetylated histones (26). In Figure 8, the Western blots show that hyperacetylated H3.3, which is purified from the treated cells, is less sensitive to degradation by 20S proteasomes than H3.3 from the control cells.…”

Polyaminohydroxamic Acids and Polyaminobenzamides as Isoform Selective Histone Deacetylase Inhibitors

“…8 The synthetic routes to PABA analogues 21-23 are shown in Schemes 1 and 2. Our initial strategy involved N-Boc protection 14 of 4-(amino)methylbenzoic acid 24, followed by coupling with o-nitroaniline (EDCI, HOBT, TEA) to form 25.…”

“…8 The results of these studies are summarized in Table 1. PAHAs 6, 8, 9, 13, 17, 18, and 20 all produced greater than 50% inhibition, with compound 18 producing the greatest inhibition (88.7%).…”

“…Using these design criteria, we successfully identified three lead compounds from a library consisting of only 16 analogues. 8 We now report 15 additional analogues in the PAHA series (compounds 6-20) and have extended our studies to include polyaminobenzamides (PABAs) 21-23, which incorporate the benzamide moiety of 2 and also possess HDAC inhibitory activity in vitro.…”

Targeting Transcriptional Dysregulation in Huntington’s Disease: Description of Therapeutic Approaches

“…Attaching them to proteins provides an elegant way to manipulate charge concentrations locally and alter DNA binding affinity (highly negatively charged due to phosphate backbone) to assume a compact (silenced) conformation. Recent papers showed that polyamines or polyamines analogs inhibit Lysine Specific Demethylase 1 (LSD1), a FADdependent histone demethylases, able to demethylate mono and dimethyl lysine 4 of histone H3, active marks of transcription (Huang et al, 2007;Shi et al, 2004) and they can block HDACs activity sitting in their catalytic pocket (Varghese et al, 2005). In a number of in vitro studies, polyamines can be crosslinked to glutamine tails of histones by transglutaminase 2 (TGase 2).…”