The Fungal Metabolite Eurochevalierine, a Sequiterpene Alkaloid, Displays Anti-Cancer Properties through Selective Sirtuin 1/2 Inhibition.

Abstract

NAD⁺-dependent histone deacetylases (sirtuins) are implicated in cellular processes such as proliferation, DNA repair, and apoptosis by regulating gene expression and the functions of numerous proteins. Due to their key role in cells, the discovery of small molecule sirtuin modulators has been of significant interest for diverse therapeutic applications. In particular, it has been shown that inhibition of sirtuin 1 and 2 activities is beneficial for cancer treatment. Here, we demonstrate that the fungal metabolite eurochevalierine from the fungus Neosartorya pseudofischeri inhibits sirtuin 1 and 2 activities (IC50 about 10 µM) without affecting sirtuin 3 activity. The binding modes of the eurochevalierine for sirtuin 1 and 2 have been identified through computational docking analyses. Accordingly, this sequiterpene alkaloid induces histone H4 and α-tubulin acetylation in various cancer cell models in which it induces strong cytostatic effects without affecting significantly the viability of healthy PBMCs. Importantly, eurochevalierine targets preferentially cancer cell proliferation (selectivity factor ≫ 7), as normal human primary CD34⁺ stem/progenitor cells were less affected by the treatment. Finally, eurochevalierine displays suitable drug-likeness parameters and therefore represent a promising scaffold for lead molecule optimization to study the mechanism and biological roles of sirtuins and potentially a basis for development into therapeutics.

• Authors: Michael Schnekenburger, Véronique Mathieu, Florence Lefranc, Jun Young Jang, Marco Masi, Anake Kijjoa, Antonio Evidente, Hyun-Jung Kim, Robert Kiss, Mario Dicato, Byung Woo Han, Marc Diederich
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 23 Issue 2 (Feb 05 2018) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 29401749 (Publication Type: Journal Article)

Chemical References

• Alkaloids
• Antineoplastic Agents
• Histone Deacetylase Inhibitors
• Histones
• Sesquiterpenes
• Tubulin
• SIRT1 protein, human
• SIRT2 protein, human
• SIRT3 protein, human
• Sirtuin 1
• Sirtuin 2
• Sirtuin 3

Topics

• Acetylation
• Alkaloids (chemistry, isolation & purification, pharmacology)
• Antineoplastic Agents (chemistry, isolation & purification, pharmacology)
• Binding Sites
• Gene Expression Regulation, Neoplastic
• Histone Deacetylase Inhibitors (chemistry, isolation & purification, pharmacology)
• Histones (genetics, metabolism)
• Humans
• Molecular Docking Simulation
• Neosartorya (chemistry, metabolism)
• Protein Binding
• Protein Conformation, alpha-Helical
• Protein Conformation, beta-Strand
• Protein Interaction Domains and Motifs
• Protein Processing, Post-Translational
• Sesquiterpenes (chemistry, isolation & purification, pharmacology)
• Sirtuin 1 (antagonists & inhibitors, genetics, metabolism)
• Sirtuin 2 (antagonists & inhibitors, genetics, metabolism)
• Sirtuin 3 (genetics, metabolism)
• Tubulin (genetics, metabolism)