Stable reduction product of misonidazole

Area of Science:

• Chemical reduction
• Organic chemistry
• Radiochemistry

Background:

• Misonidazole (MISO) is a hypoxic cell radiosensitizer.
• Understanding MISO's reduction products is crucial for its application.
• Anaerobic reduction pathways of MISO are not fully elucidated.

Purpose of the Study:

• To identify the predominant stable product of MISO's anaerobic radiation chemical reduction.
• To synthesize and characterize this product.
• To evaluate the toxicity of the identified product.

Main Methods:

• Anaerobic radiation chemical reduction of MISO at pH 7 with formate and N2O.
• Synthesis of the cyclic guanidinium ion MISO-DDI sulfate.
• NMR spectral analysis for structural confirmation.
• Derivatization to glyoxal bis-oxime.
• In vivo (C3H mice) and in vitro (CHO cells) toxicity assays.

Main Results:

• The predominant stable product (>80%) was identified as the cyclic guanidinium ion MISO-DDI (4,5-dihydro-4,5-dihydroxyimidazolium ion).
• MISO-DDI sulfate was synthesized and characterized.
• Glyoxal bis-oxime was formed in 86% yield, confirming MISO-DDI formation.
• MISO-DDI showed lower toxicity than MISO and free glyoxal in vivo and in vitro.

Conclusions:

• MISO-DDI is the major stable product of MISO reduction under specified conditions.
• The toxicity of MISO under hypoxia may be attributed to a reactive, short-lived intermediate.
• Further research into MISO's reactive intermediates is warranted.