Efficacy of 2-halogen substituted D-glucose analogs in blocking glycolysis and killing "hypoxic tumor cells"

Theodore J. Lampidis, Metin Kurtoglu, Johnathan C. Maher, Huaping Liu, Awtar K. Ganju-Krishan, Valerie Sheft, Slawomir Szymanski, Izabela Fokt, Witold R. Rudnicki, Krzysztof Ginalski, Bogdan Lesyng, Waldemar Priebe

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52 Scopus citations


Purpose: Since 2-deoxy-D-glucose (2-DG) is currently in phase I clinical trials to selectively target slow-growing hypoxic tumor cells, 2-halogenated D-glucose analogs were synthesized for improved activity. Given the fact that 2-DG competes with D-glucose for binding to hexokinase, in silico modeling of molecular interactions between hexokinase I and these new analogs was used to determine whether binding energies correlate with biological effects, i.e. inhibition of glycolysis and subsequent toxicity in hypoxic tumor cells. Methods and Results: Using a QSAR-like approach along with a flexible docking strategy, it was determined that the binding affinities of the analogs to hexokinase I decrease as a function of increasing halogen size as follows: 2-fluoro-2-deoxy-D-glucose (2-FG) > 2-chloro-2-deoxy-D-glucose (2-CG) > 2-bromo-2-deoxy-D-glucose (2-BG). Furthermore, D-glucose was found to have the highest affinity followed by 2-FG and 2-DG, respectively. Similarly, flow cytometry and trypan blue exclusion assays showed that the efficacy of the halogenated analogs in preferentially inhibiting growth and killing hypoxic vs. aerobic cells increases as a function of their relative binding affinities. These results correlate with the inhibition of glycolysis as measured by lactate inhibition, i.e. ID50 1 mM for 2-FG, 6 mM for 2-CG and > 6 mM for 2-BG. Moreover, 2-FG was found to be more potent than 2-DG for both glycolytic inhibition and cytotoxicity. Conclusions: Overall, our in vitro results suggest that 2-FG is more potent than 2-DG in killing hypoxic tumor cells, and therefore may be more clinically effective when combined with standard chemotherapeutic protocols.

Original languageEnglish (US)
Pages (from-to)725-734
Number of pages10
JournalCancer Chemotherapy And Pharmacology
Issue number6
StatePublished - Dec 1 2006


  • 2-Deoxy-D-glucose
  • 2-Fluoro-2-deoxy-D-glucose
  • Antitumor activity
  • Glycolysis
  • Hypoxia

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

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    Lampidis, T. J., Kurtoglu, M., Maher, J. C., Liu, H., Ganju-Krishan, A. K., Sheft, V., Szymanski, S., Fokt, I., Rudnicki, W. R., Ginalski, K., Lesyng, B., & Priebe, W. (2006). Efficacy of 2-halogen substituted D-glucose analogs in blocking glycolysis and killing "hypoxic tumor cells". Cancer Chemotherapy And Pharmacology, 58(6), 725-734. https://doi.org/10.1007/s00280-006-0207-8