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The fungal metabolite eurochevalierine, a sequiterpene alkaloid, displays anti-cancer properties through selective sirtuin 1/2 inhibition

Authors :
Marco Masi
Véronique Mathieu
Hyun-Jung Kim
Marc Diederich
Michael Schnekenburger
Anake Kijjoa
Mario Dicato
Byung Woo Han
Jun Young Jang
Robert Kiss
Antonio Evidente
Florence Lefranc
Schnekenburger, Michael
Mathieu, Véronique
Lefranc, Florence
Jang, Jun Young
Masi, Marco
Kijjoa, Anake
Evidente, Antonio
Kim, Hyun-Jung
Kiss, Robert
Dicato, Mario
Han, Byung Woo
Diederich, Marc
CIIMAR - Centro Interdisciplinar de Investigação Marinha e Ambiental
Source :
Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry, Repositório Científico de Acesso Aberto de Portugal, Repositório Científico de Acesso Aberto de Portugal (RCAAP), instacron:RCAAP, Molecules, Vol 23, Iss 2, p 333 (2018), Molecules; Volume 23; Issue 2; Pages: 333, Molecules, Molecules, 23 (2
Publication Year :
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.<br />SCOPUS: ar.j<br />info:eu-repo/semantics/published

Details

Language :
English
Database :
OpenAIRE
Journal :
Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry, Repositório Científico de Acesso Aberto de Portugal, Repositório Científico de Acesso Aberto de Portugal (RCAAP), instacron:RCAAP, Molecules, Vol 23, Iss 2, p 333 (2018), Molecules; Volume 23; Issue 2; Pages: 333, Molecules, Molecules, 23 (2
Accession number :
edsair.doi.dedup.....8df5597955bf1d2b3091dd74e49dad22