Defining the Mechanism of Action and Enzymatic Selectivity of Psammaplin A against Its Epigenetic Targets was written by Baud, Matthias G. J.;Leiser, Thomas;Haus, Patricia;Samlal, Sharon;Wong, Ai Ching;Wood, Robert J.;Petrucci, Vanessa;Gunaratnam, Mekala;Hughes, Siobhan M.;Buluwela, Lakjaya;Turlais, Fabrice;Neidle, Stephen;Meyer-Almes, Franz-Josef;White, Andrew J. P.;Fuchter, Matthew J.. And the article was included in Journal of Medicinal Chemistry in 2012.Electric Literature of C12H11NO4 This article mentions the following:
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 mol. features of this mol. 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 (IC50 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. In the experiment, the researchers used many compounds, for example, 4-(1,3-Dioxoisoindolin-2-yl)butanoic acid (cas: 3130-75-4Electric Literature of C12H11NO4).
4-(1,3-Dioxoisoindolin-2-yl)butanoic acid (cas: 3130-75-4) belongs to indole derivatives. Indole is an important structural motif of various drugs, therapeutic leads besides its prevalence in numerous natural products, agrochemicals, perfumery, and dyes. It is used in perfumery and in making tryptophan, an essential amino acid, and indoleacetic acid (heteroauxin), a hormone that promotes the development of roots in plant cuttings.Electric Literature of C12H11NO4
Referemce:
Indole alkaloid derivatives as building blocks of natural products from聽Bacillus thuringiensis聽and聽Bacillus velezensis聽and their antibacterial and antifungal activity study,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles