RESUMEN
There 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.
RESUMEN
Novel picolinamide-based histone deacetylase (HDAC) inhibitors were developed, drawing inspiration from the natural product psammaplinâ A. We found that the HDAC potency and isoform selectivity provided by the oxime unit of psammaplinâ 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.
Asunto(s)
Disulfuros/química , Disulfuros/farmacología , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Picolínicos/química , Ácidos Picolínicos/farmacología , Tirosina/análogos & derivados , Amidas/química , Amidas/farmacología , Histona Desacetilasas/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Isoformas de Proteínas/metabolismo , Tirosina/química , Tirosina/farmacologíaRESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Disulfuros/farmacología , Epigénesis Genética , Inhibidores de Histona Desacetilasas/farmacología , Profármacos/farmacología , Tirosina/análogos & derivados , Acetilación , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Cristalografía por Rayos X , ADN (Citosina-5-)-Metiltransferasas/antagonistas & inhibidores , Dimerización , Disulfuros/síntesis química , Disulfuros/química , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Histonas/metabolismo , Humanos , Isoenzimas/antagonistas & inhibidores , Modelos Moleculares , Profármacos/síntesis química , Profármacos/química , Relación Estructura-Actividad , Tubulina (Proteína)/metabolismo , Tirosina/síntesis química , Tirosina/química , Tirosina/farmacologíaRESUMEN
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.