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Exploration of sugar-based inhibitors of glycolysis to target brain tumors

Waldemar Priebe 1,  Marcin Cybulski 1,2,  Sławomir Szymański ,  Izabela Skóra ,  Stanisław Skóra ,  Charles A. Conrad ,  Timothy Madden 3

1. The University of Texas M D Anderson Cancer Center, Holcombe Boulevard 1515, Houston, TX 77030, United States
2. Instytut Farmaceutyczny (PRI), Rydygiera 8, Warszawa 01-793, Poland
3. Argonne National Laboratory (ANL), 9700 South Cass Avenue, Argonne, IL 60439, United States

Abstract

Glycolysis is the major energy producing pathway for fast growing, glycolytically dependent tumors, such as gliomas and ependymomas. Blocking glycolysis is, therefore, an important and clinically unexplored therapeutic strategy when used alone or as a combination therapy to enhance the effects of chemotherapy in energy-starved tumors.

In our studies, we have examined D-glucose antimetabolites 2-deoxy-D-glucose (2-DG), 2-deoxy-2-fluoro-D-glucose (2-FG) and 2-deoxy-2-fluoro-D-mannose (2-FM) and confirmed their ability to block glycolysis and discovered their ability to induce autophagic cell death.

Our more detail evaluation revealed that these compounds do not possess sufficient drug-like properties   (reasonable biostability, pharmacokinetic characteristics, or distribution to the target) to warrant further investigations into their clinical effectiveness. In an attempt to improve the pharmacokinetic profile of 2-DG, we have designed, synthesized, and tested a series of prodrugs that enhance biostability, biodistribution, and delivery of 2-DG to its CNS target.  We will present the synthesis and preliminary evaluation of compounds, leading to the selection of WP1122 as our lead compound for further drug development.
 

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Presentation: Invited oral at VII Multidyscyplinarna Konferencja Nauki o Leku, by Waldemar Priebe
See On-line Journal of VII Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2010-03-04 09:01
Revised:   2010-03-06 10:48