Abstract
Several 2-nitroimidazole-based molecules (NIs) are used as clinical hypoxic tumor radiodiagnostics, but they are not effective as radiosensitizers/radiochemotherapeutics. These NIs permeate tumor cells nonselectively via diffusion, and in therapy, where high doses are required, their dose limiting toxicities preclude success. The synthesis and preliminary in vitro evaluations of three glucoazomycins, members of a novel class of C6-O-glucose-linked-azomycin conjugates that are putative substrates of glucose transport proteins (GLUTs) and possess hypoxia-selective radiosensitization features, are now reported. The hypoxia-dependent upregulation of several GLUTs provides a rational basis to develop these glucoazomycins because more selective uptake in hypoxic cells would decrease systemic toxicities at effective doses. Calculated partition coefficients (ClogP, -1.70 to -2.99) predict rapid in vivo clearance for low systemic toxicity. In vitro experimental data show that glucoazomycins are radiosensitizers and that they competitively inhibit glucose uptake.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Hypoxia
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Cell Line, Tumor
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Drug Design*
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Glucose Transport Proteins, Facilitative / antagonists & inhibitors
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Glucose Transport Proteins, Facilitative / metabolism*
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Glucosides / chemistry
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Glucosides / pharmacokinetics*
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Glucosides / pharmacology
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Glycosides / chemical synthesis
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Glycosides / pharmacokinetics*
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Glycosides / pharmacology
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Humans
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Inhibitory Concentration 50
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Magnetic Resonance Spectroscopy
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Misonidazole / analogs & derivatives
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Misonidazole / chemistry
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Neoplasms / diagnostic imaging*
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Neoplasms / drug therapy
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Neoplasms / radiotherapy*
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Nitroimidazoles / chemical synthesis
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Nitroimidazoles / chemistry
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Nitroimidazoles / pharmacokinetics*
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Nitroimidazoles / pharmacology
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Radiation-Sensitizing Agents / chemistry
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Radiation-Sensitizing Agents / pharmacokinetics*
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Radiation-Sensitizing Agents / pharmacology
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Radionuclide Imaging
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Radiopharmaceuticals / chemistry
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Radiopharmaceuticals / pharmacokinetics*
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Transcriptional Activation / drug effects
Substances
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6-((9-(2-nitro-1H-imidazol-1-yl)allyloxy)methyl)glucopyranose
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6-O-(9-(2-nitro-1H-imidazolyl)-8-fluoropropyl)glucopyranose
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6-O-(9-(2-nitro-1H-imidazolyl)-8-hydroxypropyl)glucopyranose
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Glucose Transport Proteins, Facilitative
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Glucosides
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Glycosides
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Nitroimidazoles
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Radiation-Sensitizing Agents
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Radiopharmaceuticals
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fluoromisonidazole
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iodoazomycin arabinoside
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fluoroazomycin arabinoside
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Misonidazole