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 Krishan, Valerie Sheft, Slawomir Szymanski, Izabela Fokt, Witold R. Rudnicki, Krzysztof Ginalski, Bogdan Lesyng, Waldemar Priebe

Research output: Contribution to journalArticlepeer-review

57 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 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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