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.


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.