Please use this identifier to cite or link to this item:
https://hdl.handle.net/10216/120520
Author(s): | Schnekenburger M. Mathieu V. Lefranc F. Jang J.Y. Masi M. Kijjoa A. Evidente A. Kim H.-J. Kiss R. Dicato M. Han B.W. Diederich M. |
Title: | The fungal metabolite eurochevalierine, a sequiterpene alkaloid, displays anti-cancer properties through selective sirtuin 1/2 inhibition |
Publisher: | MDPI |
Issue Date: | 2018 |
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. © 2018 by the authors. |
Subject: | alkaloid antineoplastic agent histone histone deacetylase inhibitor protein binding sesquiterpene SIRT1 protein, human SIRT2 protein, human SIRT3 protein, human sirtuin 1 sirtuin 2 sirtuin 3 tubulin acetylation alpha helix antagonists and inhibitors beta sheet binding site chemistry gene expression regulation genetics human isolation and purification metabolism molecular docking Neosartorya protein domain protein processing Acetylation Alkaloids Antineoplastic Agents Binding Sites Gene Expression Regulation, Neoplastic Histone Deacetylase Inhibitors Histones Humans Molecular Docking Simulation Neosartorya Protein Binding Protein Conformation, alpha-Helical Protein Conformation, beta-Strand Protein Interaction Domains and Motifs Protein Processing, Post-Translational Sesquiterpenes Sirtuin 1 Sirtuin 2 Sirtuin 3 Tubulin |
URI: | https://hdl.handle.net/10216/120520 |
Source: | Molecules, vol. 23(2):333 |
Document Type: | Artigo em Revista Científica Internacional |
Rights: | openAccess |
Appears in Collections: | CIIMAR - Artigo em Revista Científica Internacional |
Files in This Item:
File | Description | Size | Format | |
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Schnekenburger M_2018.pdf | 2.6 MB | Adobe PDF | View/Open |
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