Please use this identifier to cite or link to this item:
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 deacetylase inhibitor
protein binding
SIRT1 protein, human
SIRT2 protein, human
SIRT3 protein, human
sirtuin 1
sirtuin 2
sirtuin 3
alpha helix
antagonists and inhibitors
beta sheet
binding site
gene expression regulation
isolation and purification
molecular docking
protein domain
protein processing
Antineoplastic Agents
Binding Sites
Gene Expression Regulation, Neoplastic
Histone Deacetylase Inhibitors
Molecular Docking Simulation
Protein Binding
Protein Conformation, alpha-Helical
Protein Conformation, beta-Strand
Protein Interaction Domains and Motifs
Protein Processing, Post-Translational
Sirtuin 1
Sirtuin 2
Sirtuin 3
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 SizeFormat 
Schnekenburger M_2018.pdf2.6 MBAdobe PDFThumbnail

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.