Psammaplin A (11c) is a marine metabolite previously reported to be a potent inhibitor of two classes of epigenetic enzymes: histone deacetylases and DNA methyltransferases. The design and synthesis of a focused library based on the psammaplin A core has been carried out to probe the molecular features of this molecule responsible for its activity. By direct in vitro assay of the free thiol generated upon reduction of the dimeric psammaplin scaffold, we have unambiguously demonstrated that 11c functions as a natural prodrug, with the reduced form being highly potent against HDAC1 in vitro (IC(50) 0.9 nM). Furthermore, we have shown it to have high isoform selectivity, being 360-fold selective for HDAC1 over HDAC6 and more than 1000-fold less potent against HDAC7 and HDAC8. SAR around our focused library revealed a number of features, most notably the oxime functionality to be important to this selectivity. Many of the compounds show significant cytotoxicity in A549, MCF7, and W138 cells, with the SAR of cytotoxicity correlating to HDAC inhibition. Furthermore, compound treatment causes upregulation of histone acetylation but little effect on tubulin acetylation. Finally, we have found no evidence for 11c functioning as a DNMT inhibitor.
New synthetic routes towards the natural product psammaplin A were developed with the particular view to preparing diverse analogues for biological assessment. These routes utilize cheap and commercially available starting materials, and allowed access to psammaplin A analogues not accessible via currently reported methods. Preliminary biological studies revealed these compounds to be the most potent non peptidic inhibitors of the enzyme histone deacetylase 1 (HDAC1, class I) discovered so far. Interestingly, psammaplin A and our synthetic analogues show class I selectivity in vitro, an important feature for the design and synthesis of future isoform selective inhibitors.
Novel picolinamide-based histone deacetylase (HDAC) inhibitors were developed, drawing inspiration from the natural product psammaplin A. We found that the HDAC potency and isoform selectivity provided by the oxime unit of psammaplin A could be reproduced by using carefully chosen heterocyclic frameworks. The resulting (hetero)aromatic amide based compounds displayed very high potency and isoform selectivity among the HDAC family, in addition to excellent ligand efficiency relative to previously reported HDAC inhibitors. In particular, the high HDAC1 isoform selectivity provided by the chloropyridine motif represents a valuable design criterion for the development of new lead compounds and chemical probes that target HDAC1.
SummaryThere has been significant interest in the bioactivity of the natural product psammaplin A, most recently as a potent and isoform selective HDAC inhibitor. Here we report our preliminary studies on thioester HDAC inhibitors derived from the active monomeric (thiol) form of psammaplin A, as a means to improve compound delivery into cells. We have discovered that such compounds exhibit both potent cytotoxicity and enzymatic inhibitory activity against recombinant HDAC1. The latter effect is surprising since previous SAR suggested that modification of the thiol functionality should detrimentally affect HDAC potency. We therefore also report our preliminary studies on the mechanism of action of this observed effect.
Naturally isolated products continue to play a significant role in anticancer drug discovery. In line with our interest in small molecule compounds which effect epigenetic gene regulation, we are interested in the structural and biological properties of the natural product Psammaplin A. While it has been implicated as an inhibitor of numerous targets such as mycothiol-S-conjugate amidase, topoisomerase II and aminopeptidase N, studies by Crews and co-workers showed it to be an extremely potent inhibitor of both histone deacetylase (HDAC) and DNA methyltransferase (DNMT) enzymes. Our goal was to establish structure-activity relationships around psammaplin A, probing the molecular features responsible for the chemical biology of this natural product. We developed a number of versatile synthetic routes towards small compound libraries based on the psammaplin core [1]. We subsequently assessed the activity of these compounds against a selection of histone deacetylases, DNMT1, and in cell based assays. Analysis of the data revealed psammaplin A to be a natural prodrug; the central disulphide being reduced to a free thiol. Indeed, we showed the corresponding thiol not only to be a potent inhibitor of HDAC1 (IC50 0.001 μM), but to have remarkable selectivity against HDAC6 (IC50 0.360 μM), HDAC7 (IC50 17.4 μM) and HDAC8 (IC50 1.34 μM) in cell-free assays. Cell-based (MCF7) studies confirmed the HDAC targeting potential of psammaplin A and confirmed the selectivity observed in vitro. Curiously, our psammaplin A derivatives demonstrated no activity against DNMT1 in cell-free assays. Taken together with other reports, this data suggests psammaplin A may not be an inhibitor of DNMT1 as previously reported. In conclusion, we have explored the epigenetic activity of psammaplin A and have found it to have significant potency and selectivity against HDACs, whereas we find no evidence for DNMT1 activity. Reference: 1. “New synthetic strategies towards Psammaplin A, access to natural product analogues” Baud, M. G. J.; Leiser, T.; Meyer-Almes, F.-J.; Fuchter, M. J. Org. Biomol. Chem. 2011, 9, 659–662. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B166.
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