6-Diazo-5-oxo-L-norleucine (DON) is a

glutamine Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral ...

antagonist, which was isolated originally from Streptomyces in a sample of Peruvian soil. This

diazo compound The diazo group is an organic moiety consisting of two linked nitrogen atoms ( azo) at the terminal position. Overall charge neutral organic compounds containing the diazo group bound to a carbon atom are called diazo compounds or diazoalkanes ...

is biosynthesized from lysine by three enzymes in bacteria. It is one of the most famous

non-proteinogenic amino acid In biochemistry, non-coded or non-proteinogenic amino acids are distinct from the 22 proteinogenic amino acids (21 in eukaryotesplus formylmethionine in eukaryotes with prokaryote organelles like mitochondria) which are naturally encoded in the ge ...

and was characterized in 1956 by Henry W Dion et al., who suggested a possible use in cancer therapy. This antitumoral efficacy was confirmed in different animal models. DON was tested as chemotherapeutic agent in different clinical studies, but was never approved. In 2019, DON was shown to kill tumor cells while reversing disease symptoms and improve overall survival in late-stage experimental

glioblastoma Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ...

in mice, when combined with calorie-restricted

ketogenic diet The ketogenic diet is a high- fat, adequate-protein, low-carbohydrate dietary therapy that in conventional medicine is used mainly to treat hard-to-control (refractory) epilepsy in children. The diet forces the body to burn fats rather than ca ...

Chemistry

DON is a water-soluble yellowish powder, which can be dissolved also in aqueous solutions of methanol,

acetone Acetone (2-propanone or dimethyl ketone), is an organic compound with the formula . It is the simplest and smallest ketone (). It is a colorless, highly volatile and flammable liquid with a characteristic pungent odour. Acetone is miscib ...

ethanol Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an alcohol with the chemical formula . Its formula can be also written as or (an ethyl group linked to a ...

, but dissolution in absolute alcohols is difficult. Solutions of at least 50 μM DON in 0.9% NaCl are lightly yellowish. The crystalline form appears as yellowish greenish needles. The specific rotation is �sub>26^D +21° (c = 5.4% in H₂O). In phosphate buffer, pH 7 are the ultraviolet absorption maxima at 274 nm (E1%1 cm. 683) and 244 nm (E1%1 cm 376).

Biochemistry

DON is used as inhibitor of different glutamine utilizing enzymes. Due to its similarity to glutamine it can enter catalytic centres of these enzymes and inhibits them by covalent binding, or more precisely by

alkylation Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecti ...

. The following table gives a survey of DON targets.

Pharmacology

DON is a cytotoxic inhibitor of many enzymes of

nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecule ...

synthesis. It could be shown ''in vitro'' that DON treatment led to apoptosis, the programmed cell death. Different pathways were investigated. So it could be shown that the inner mitochondrial membrane was damaged, and single strand DNA breaks were observed. The exact mode of action remains unclear and needs further research. DON is not approved as pharmaceutical agent, but is tested in combination with a recombinant glutaminase in clinical trials for the treatment of different solid tumors.

References

{{DEFAULTSORT:Diazo-5-oxo-L-norleucine, 6- Experimental cancer drugs Amino acids Diazo compounds Conjugated ketones