Back to Search Start Over

Potent Biological Activity of Fluorinated Derivatives of 2-Deoxy-d-Glucose in a Glioblastoma Model

Authors :
Maja Sołtyka-Krajewska
Marcin Ziemniak
Anna Zawadzka-Kazimierczuk
Paulina Skrzypczyk
Ewelina Siwiak-Niedbalska
Anna Jaśkiewicz
Rafał Zieliński
Izabela Fokt
Stanisław Skóra
Wiktor Koźmiński
Krzysztof Woźniak
Waldemar Priebe
Beata Pająk-Tarnacka
Source :
Biomedicines, Vol 12, Iss 10, p 2240 (2024)
Publication Year :
2024
Publisher :
MDPI AG, 2024.

Abstract

Background: One defining feature of various aggressive cancers, including glioblastoma multiforme (GBM), is glycolysis upregulation, making its inhibition a promising therapeutic approach. One promising compound is 2-deoxy-d-glucose (2-DG), a d-glucose analog with high clinical potential due to its ability to inhibit glycolysis. Upon uptake, 2-DG is phosphorylated by hexokinase to 2-DG-6-phosphate, which inhibits hexokinase and downstream glycolytic enzymes. Unfortunately, therapeutic use of 2-DG is limited by poor pharmacokinetics, suppressing its efficacy. Methods: To address these issues, we synthesized novel halogenated 2-DG analogs (2-FG, 2,2-diFG, 2-CG, and 2-BG) and evaluated their glycolytic inhibition in GBM cells. Our in vitro and computational studies suggest that these derivatives modulate hexokinase activity differently. Results: Fluorinated compounds show the most potent cytotoxic effects, indicated by the lowest IC50 values. These effects were more pronounced in hypoxic conditions. 19F NMR experiments and molecular docking confirmed that fluorinated derivatives bind hexokinase comparably to glucose. Enzymatic assays demonstrated that all halogenated derivatives are more effective HKII inhibitors than 2-DG, particularly through their 6-phosphates. By modifying the C-2 position with halogens, these compounds may overcome the poor pharmacokinetics of 2-DG. The modifications seem to enhance the stability and uptake of the compounds, making them effective at lower doses and over prolonged periods. Conclusions: This research has the potential to reshape the treatment landscape for GBM and possibly other cancers by offering a more targeted, effective, and metabolically focused therapeutic approach. The application of halogenated 2-DG analogs represents a promising advancement in cancer metabolism-targeted therapies, with the potential to overcome current treatment limitations.

Details

Language :
English
ISSN :
22279059
Volume :
12
Issue :
10
Database :
Directory of Open Access Journals
Journal :
Biomedicines
Publication Type :
Academic Journal
Accession number :
edsdoj.6d606b7bd79e4c7ba8de139e5102bb5f
Document Type :
article
Full Text :
https://doi.org/10.3390/biomedicines12102240