Amaryllidaceae Alkaloids as Potential Glycogen Synthase Kinase-3β Inhibitors.

Daniela Hulcová,Marcela Šafratová,Anna Hošťálková,Kamila Klímová,Lucie Cahlíková,Kateřina Breiterová,Tomáš Siatka,Angela De Simone,Vincenza Andrisano,Lara Davani

doi:10.3390/molecules23040719

Daniela Hulcová, Marcela Šafratová + Show 8 more

Open Access

https://doi.org/10.3390/molecules23040719

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Abstract

Glycogen synthase kinase-3β (GSK-3β) is a multifunctional serine/threonine protein kinase that was originally identified as an enzyme involved in the control of glycogen metabolism. It plays a key role in diverse physiological processes including metabolism, the cell cycle, and gene expression by regulating a wide variety of well-known substances like glycogen synthase, tau-protein, and β-catenin. Recent studies have identified GSK-3β as a potential therapeutic target in Alzheimer´s disease, bipolar disorder, stroke, more than 15 types of cancer, and diabetes. GSK-3β is one of the most attractive targets for medicinal chemists in the discovery, design, and synthesis of new selective potent inhibitors. In the current study, twenty-eight Amaryllidaceae alkaloids of various structural types were studied for their potency to inhibit GSK-3β. Promising results have been demonstrated by alkaloids of the homolycorine-{9-O-demethylhomolycorine (IC50 = 30.00 ± 0.71 µM), masonine (IC50 = 27.81 ± 0.01 μM)}, and lycorine-types {caranine (IC50 = 30.75 ± 0.04 μM)}.

Highlights

Glycogen synthase kinase-3β (GSK-3β) is a ubiquitous pleiotropic serine/threonine kinase that plays crucial roles in cellular functions, including cell-cycle regulation, differentiation, and proliferation, and gene expression by regulating a wide variety of known targets such as glycogen synthase, τ-protein, and β-catenin [1]
Phosphorylation of τ-proteins is primarily dependent on GSK-3β and cyclin-dependent kinase 5 (CDK5) [9]
In our search for active natural products against neurological and cancer disorders, we have discovered the potency of Amaryllidaceae alkaloids to inhibit GSK-3β

Summary

Introduction

Glycogen synthase kinase-3β (GSK-3β) is a ubiquitous pleiotropic serine/threonine kinase that plays crucial roles in cellular functions, including cell-cycle regulation, differentiation, and proliferation, and gene expression by regulating a wide variety of known targets such as glycogen synthase, τ-protein, and β-catenin [1]. Double-blind, placebo-controlled, randomized, escalating dose trial, 30 patients with mild to moderate Alzheimers disease were enrolled and received either tideglusib or placebo (orally) at escalating doses for a total of 20 weeks The objective of this pilot study was to evaluate safety and tolerability of tideglusib with strict criteria for drug escalation or withdrawal. Amaryllidaceae alkaloids, consisting of a nitrogen-containing polycyclic structure, are produced exclusively by plants of the Amaryllidaceae family These compounds have attracted considerable attention, most prominently because of their inhibition of acetylcholinesterase (AChE) and activity against drug-resistant cancers with dismal prognoses [27,28,29,30]. In our search for active natural products against neurological and cancer disorders, we have discovered the potency of Amaryllidaceae alkaloids to inhibit GSK-3β

Amaryllidaceae Alkaloids

Potency of Amaryllidaceae Alkaloids to Inhibit GSK-3β

GSK-3β Assay

Conclusions