6-Diazo-5-oxo-L-norleucine

6-Diazo-5-oxo-L-norleucine (DON) is a small molecule antibiotic originally isolated from Streptomyces. It is a non-proteinogenic amino acid and a potent glutamine antagonist. Its mechanism of action involves the irreversible inhibition of various glutamine-utilizing enzymes, including glutaminase, glutamine amidotransferases, CTP synthase, FGAR amidotransferase, NAD(+) synthase, GMP synthase, asparagine synthase, and 2-N-amidotransferase. This inhibition disrupts glutamine metabolism, which is crucial for nucleotide synthesis and cellular energy production, leading to mitochondrial damage and apoptosis in cancer cells. DON has demonstrated anticancer, analgesic, antibacterial, and antiviral properties. It was investigated as a chemotherapeutic agent in clinical studies for various cancers but was never approved due to dose-limiting systemic toxicities, particularly gastrointestinal. Current research efforts are focused on developing prodrug strategies to enhance its therapeutic index and achieve targeted delivery, especially for conditions like glioblastoma, to overcome its previous limitations.

Other names

DiazooxonorleucineL-6-Diazo-5-oxonorleucineL6-Diazo-5-oxonorleucineL 6-Diazo-5-oxonorleucineNSC 7365NSC7365NSC-73656-Diazo-5-oxo-L-nor-Leucine