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Molecules 2018, 23(2), 333; doi:10.3390/molecules23020333

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

Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg
Department of Pharmacotherapy and Pharmaceutics, Faculté de Pharmacie, Université Libre de Bruxelles, Boulevard du Triomphe, 1050 Brussels, Belgium
Service de Neurochirurgie, Hôpital Erasme, Université Libre de Bruxelles, 808 Route de Lennik, 1070 Brussels, Belgium
Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, 1 Gwanak-ro Gwanak-gu, Seoul 08826, Korea
Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Via Cintia 4, 80126 Napoli, Italy
Instituto de Ciências Biomédicas de Abel Salazar (ICBAS) and CIIMAR, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
College of Pharmacy, Chung-Ang University, 84 Heukseok-ro Dongjak-gu, Seoul 06974, Korea
Retired – previously Director of Research at the Fonds National de la Recherche Scientifique (FRS-FNRS; Belgium)
Authors to whom correspondence should be addressed.
Received: 12 January 2018 / Revised: 29 January 2018 / Accepted: 31 January 2018 / Published: 5 February 2018
(This article belongs to the Special Issue Modulators of Histone Acetylation: A Medicinal Chemistry Perspective)
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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. View Full-Text
Keywords: cancer; epigenetics; HDAC; sirtuin inhibitor; natural compound; eurochevalierine; cytostatic compound. cancer; epigenetics; HDAC; sirtuin inhibitor; natural compound; eurochevalierine; cytostatic compound.

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

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. The Fungal Metabolite Eurochevalierine, a Sequiterpene Alkaloid, Displays Anti-Cancer Properties through Selective Sirtuin 1/2 Inhibition. Molecules 2018, 23, 333.

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