Natural products as novel scaffolds for the design of glycogen synthase kinase 3β inhibitors

ABSTRACT

Introduction

The different and relevant roles of GSK-3 are of critical importance since they deal with development, metabolic homeostasis, cell polarity and fate, neuronal growth and differentiation as well as modulation of apoptotic potential. Given their involvement with different diseases, many investigations have been undertaken with the aim of discovering new and promising inhibitors for this target. In this context, atural products represent an invaluable source of active molecules.

Areas covered

In order to overcome issues such as poor pharmacokinetic properties or efficacy, frequently associated with natural compounds, different GSK-3β inhibitors belonging to alkaloid or flavonoid classes have been subjected to structural modifications in order to obtain more potent and safer compounds. Herein, the authors report the results obtained from studies where natural compounds have been used as hits with the aim of providing new kinase inhibitors endowed with a better inhibitory profile.

Expert opinion

Structurally modification of natural scaffolds is a proven approach taking advantage of their pharmacological characteristics. Indeed, whatever the strategy adopted is and, despite the limitations associated with the structural complexity of natural products, the authors recommend the use of natural scaffolds as a promising strategy for the discovery of novel and potent GSK-3β inhibitors.

KEYWORDS:

• GSK-3β
• natural scaffolds
• SAR
• inhibitors
• semisynthetic modification

Article highlights

• The involvement of GSK-3β in many pathways makes it a very attractive target to be addressed in different diseases;

• Natural products represent an invaluable source of active compounds. In particular, many compounds of marine origin are potent and characterized GSK-3β inhibitors;

• Active compounds of natural origin endowed of pharmacological properties may show some drawbacks related to their poor pharmacokinetic profile or limited efficacy, as well as the problems related to their supply;

• Structural modification of natural scaffolds is a strategy to be pursued in order to overcome issues related to natural products endowed with pharmacological activity;

• Total or semisynthetic modification as well as SAR-based modification represent proven strategies to obtain more selective and potent GSK-3β inhibitors from natural compounds belonging to alkaloids or flavonoids.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded