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.

Biosynthesis of Terpenoid–Pyrrolobenzoxazine Hybrid Natural Product CJ‐12662

“…Uncovering the enzymatic basis of biosynthesis can therefore lead to improved strategies for complexity generation and new biocatalysis candidates. Towards this goal, we have focused on the biosynthesis of CJ‐12662 ( 1 ), [7, 8] a potent anthelmintic and ectoparasiticidal natural product produced by Aspergillus fischeri var. thermomutatus ATCC 18618 (Figure 1A) [9–12] .…”

Sirtuins in Alzheimer’s Disease: SIRT2-Related GenoPhenotypes and Implications for PharmacoEpiGenetics

“…The fungal metabolite eurochevalierine, from the Neosartorya pseudofischeri fungus, inhibits sirtuin 1 and 2 activities without affecting sirtuin 3 activity. This sesquiterpene alkaloid induces histone H4 and α-tubulin acetylation in various cancer cell models, showing strong cytostatic effects [ 197 ].…”

Synergistic AML Cell Death Induction by Marine Cytotoxin (+)-1(R), 6(S), 1’(R), 6’(S), 11(R), 17(S)-Fistularin-3 and Bcl-2 Inhibitor Venetoclax

“…PBMCs and platelets (Red Cross, Luxembourg, Luxembourg) from human healthy donors were isolated and cultured as previously described [6,62]. Human primary CD34 + progenitor/stem cells were isolated from cord blood of healthy donors and cultured as previously described [63]. All cells were cultured at 37 °C in humid atmosphere and 5% CO 2 .…”