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Antibiotics and Chemotherapy 1971
Review
Topics: Amino Acids; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antineoplastic Agents; Azaserine; Bacteria; Binding, Competitive; Chick Embryo; Glutamine; Humans; Rickettsia; Shikimic Acid; Streptomyces; Viruses
PubMed: 4951003
DOI: 10.1159/000392366 -
IARC Monographs on the Evaluation of... 1976
Review
Topics: Animals; Azaserine; Carcinogens; Drug Evaluation, Preclinical; Female; Lethal Dose 50; Mice; Neoplasms, Experimental; Pregnancy; Rats; Teratogens
PubMed: 791808
DOI: No ID Found -
Azaserine, DON, and azotomycin: three diazo analogs of L-glutamine with clinical antitumor activity.Cancer Treatment Reports Jun 1979A review of the clinical data on azaserine, DON, and azotomycin reveals that these agents have limited but definite antitumor activity. All three drugs are analogs of... (Review)
Review
A review of the clinical data on azaserine, DON, and azotomycin reveals that these agents have limited but definite antitumor activity. All three drugs are analogs of L-glutamine and contain a diazo group. They have been studied as single agents in a wide variety of human malignancies and have also been included in trials using combination chemotherapy. Most of these studies were performed early in the history of clinical trials and, therefore, the method of reporting results and the evaluation criteria were quite different from those in use today. A renewed interest in these agents has been triggered by the remarkable activity of DON and azotomycin against human tumor lines implanted into nude mice. On the basis of this activity and the clinical data we have compiled, we feel that new clinical trials with these agents are warranted.
Topics: Animals; Antineoplastic Agents; Azaserine; Azo Compounds; Colonic Neoplasms; Diazooxonorleucine; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms; Neoplasms, Experimental; Transplantation, Heterologous
PubMed: 380801
DOI: No ID Found -
Chemical Research in Toxicology Jun 2021The -alkylguanosine adduct -carboxymethyldeoxyguanosine (-CMdG) has been detected at elevated levels in blood and tissue samples from colorectal cancer patients and from...
The -alkylguanosine adduct -carboxymethyldeoxyguanosine (-CMdG) has been detected at elevated levels in blood and tissue samples from colorectal cancer patients and from healthy volunteers after consuming red meat. The diazo compound l-azaserine leads to the formation of -CMdG as well as the corresponding methyl adduct -methyldeoxyguanosine (-MedG) in cells and is therefore in wide use as a chemical probe in cellular studies concerning DNA damage and mutation. However, there remain knowledge gaps concerning the chemical basis of DNA adduct formation by l-azaserine. To characterize -CMdG formation by l-azaserine, we carried out a combination of chemical and enzymatic stability and reactivity studies supported by liquid chromatography tandem mass spectrometry for the simultaneous quantification of -CMdG and -MedG. We found that l-azaserine is stable under physiological and alkaline conditions as well as in active biological matrices but undergoes acid-catalyzed hydrolysis. We show, for the first time, that l-azaserine reacts directly with guanosine (dG) and oligonucleotides to form an -serine-CMdG (-Ser-CMdG) adduct. Moreover, by characterizing the reaction of dG with l-azaserine, we demonstrate that -Ser-CMdG forms as an intermediate that spontaneously decomposes to form -CMdG. Finally, we quantified levels of -CMdG and -MedG in a human cell line exposed to l-azaserine and found maximal adduct levels after 48 h. The findings of this work elucidate the chemical basis of how l-azaserine reacts with deoxyguanosine and support its use as a chemical probe for N-nitroso compound exposure in carcinogenesis research, particularly concerning the identification of pathways and factors that promote adduct formation.
Topics: Alkylation; Animals; Azaserine; Cells, Cultured; Deoxyguanosine; Humans; Hydrogen-Ion Concentration; Molecular Structure; Swine
PubMed: 34061515
DOI: 10.1021/acs.chemrestox.0c00471 -
Nature May 2023Biosynthesis is an environmentally benign and renewable approach that can be used to produce a broad range of natural and, in some cases, new-to-nature products....
Biosynthesis is an environmentally benign and renewable approach that can be used to produce a broad range of natural and, in some cases, new-to-nature products. However, biology lacks many of the reactions that are available to synthetic chemists, resulting in a narrower scope of accessible products when using biosynthesis rather than synthetic chemistry. A prime example of such chemistry is carbene-transfer reactions. Although it was recently shown that carbene-transfer reactions can be performed in a cell and used for biosynthesis, carbene donors and unnatural cofactors needed to be added exogenously and transported into cells to effect the desired reactions, precluding cost-effective scale-up of the biosynthesis process with these reactions. Here we report the access to a diazo ester carbene precursor by cellular metabolism and a microbial platform for introducing unnatural carbene-transfer reactions into biosynthesis. The α-diazoester azaserine was produced by expressing a biosynthetic gene cluster in Streptomyces albus. The intracellularly produced azaserine was used as a carbene donor to cyclopropanate another intracellularly produced molecule-styrene. The reaction was catalysed by engineered P450 mutants containing a native cofactor with excellent diastereoselectivity and a moderate yield. Our study establishes a scalable, microbial platform for conducting intracellular abiological carbene-transfer reactions to functionalize a range of natural and new-to-nature products and expands the scope of organic products that can be produced by cellular metabolism.
Topics: Azaserine; Biological Products; Multigene Family; Styrene; Cyclopropanes; Coenzymes; Biocatalysis; Cytochrome P-450 Enzyme System
PubMed: 37138074
DOI: 10.1038/s41586-023-06027-2 -
Angewandte Chemie (International Ed. in... Jul 2023Azaserine is a bacterial metabolite containing a biologically unusual and synthetically enabling α-diazoester functional group. Herein, we report the discovery of the...
Azaserine is a bacterial metabolite containing a biologically unusual and synthetically enabling α-diazoester functional group. Herein, we report the discovery of the azaserine (aza) biosynthetic gene cluster from Glycomyces harbinensis. Discovery of related gene clusters reveals previously unappreciated azaserine producers, and heterologous expression of the aza gene cluster confirms its role in azaserine assembly. Notably, this gene cluster encodes homologues of hydrazonoacetic acid (HYAA)-producing enzymes, implicating HYAA in α-diazoester biosynthesis. Isotope feeding and biochemical experiments support this hypothesis. These discoveries indicate that a 2-electron oxidation of a hydrazonoacetyl intermediate is required for α-diazoester formation, constituting a distinct logic for diazo biosynthesis. Uncovering this biological route for α-diazoester synthesis now enables the production of a highly versatile carbene precursor in cells, facilitating approaches for engineering complete carbene-mediated biosynthetic transformations in vivo.
Topics: Azaserine; Biosynthetic Pathways; Methane; Oxidation-Reduction; Multigene Family
PubMed: 37151182
DOI: 10.1002/anie.202304646 -
Mutation Research Nov 1984Azaserine causes DNA damage in stationary-phase cells. In our investigation of this damage, we used strains of Escherichia coli differing in repair capabilities to study...
Azaserine causes DNA damage in stationary-phase cells. In our investigation of this damage, we used strains of Escherichia coli differing in repair capabilities to study azaserine-induced DNA damage, detected as DNA strand breaks by sucrose gradient sedimentation techniques. Reduced sedimentation in alkaline and neutral sucrose gradients indicated the presence of both alkali-labile sites and in situ strand breaks. Azaserine induced DNA single-strand breaks (SSBs) abundantly in all but the recA strain, in which SSBs were greatly reduced. Treatment of purified DNA with azaserine from bacteriophages T4 and PM2 produced no detectable SSBs. Several other studies also failed to detect DNA damage induced directly by azaserine. Increased levels of beta-galactosidase were induced in an E. coli strain possessing a rec::lac fusion, providing further evidence for azaserine induction of the recA gene product. In addition, azaserine induced adaptation against killing but not against mutagenesis in wild-type E. coli strain.
Topics: Azaserine; Cell-Free System; DNA Repair; DNA, Bacterial; Escherichia coli; Gene Expression Regulation; Hydrolysis; Mutation; Rec A Recombinases
PubMed: 6390189
DOI: 10.1016/0027-5107(84)90148-9 -
Antibiotics & Chemotherapy (Northfield,... Jul 1954
Topics: Azaserine; Bacteria; Fungi; Serine; Viruses
PubMed: 24543177
DOI: No ID Found -
International Journal of Experimental... Aug 1990In the rat, when pancreatic growth is stimulated there is an increased incidence of spontaneous pancreatic neoplasms and marked potentiation of the pancreatic carcinogen...
In the rat, when pancreatic growth is stimulated there is an increased incidence of spontaneous pancreatic neoplasms and marked potentiation of the pancreatic carcinogen azaserine. Since previous studies showed that cholestyramine caused pancreatic growth in this species we have now studied the effect of azaserine in rats fed soya flour diets containing cholestyramine. Two groups, each of eight rats, were fed either heated soya flour (HSF) or raw soya flour (RSF). Two further groups, each of 12 rats, received the same diets containing 2% cholestyramine (HSF + C, RSF + C). In each group, four rats received azaserine (30 mg/kg i.p.) and the remainder saline, weekly, for the first 5 weeks. Animals were killed after 24 weeks and pancreatic growth and the number and size of pancreatic neoplastic nodules was measured. RSF caused a significant increase in pancreatic weight, protein, RNA and DNA, compared with HSF and cholestyramine caused a further significant increase in pancreatic weight, protein and RNA but not DNA. Azaserine did not affect pancreatic growth. In azaserine-injected rats significantly more nodules were seen and the nodules were larger and the tumour burden greater in rats fed HSF + C than in rats fed HSF alone. However, the nodule count and other nodule parameters were not significantly different in RSF and RSF + C fed rats. It is concluded that 2% cholestyramine enhances pancreatic growth when added to soya flour diets and in rats fed HSF it potentiates the action of azaserine on the pancreas. It does not increase the potentiation of azaserine seen with RSF up to 24 weeks.
Topics: Animals; Azaserine; Cholestyramine Resin; DNA; Drug Synergism; Male; Organ Size; Pancreas; Pancreatic Neoplasms; Plant Proteins, Dietary; Proteins; Rats; Soybean Proteins
PubMed: 2400737
DOI: No ID Found -
Organic Letters Jun 2023Azaserine () is a natural product and nonproteinogenic amino acid containing a diazo group. Here we report the biosynthetic gene cluster for from . We then use isotopic...
Azaserine () is a natural product and nonproteinogenic amino acid containing a diazo group. Here we report the biosynthetic gene cluster for from . We then use isotopic feeding, gene deletion, and biochemical experiments to support a pathway whereby hydrazinoacetic acid () and a peptidyl carrier protein-loaded serine () are intermediates on route to the final natural product .
Topics: Azaserine; Serine; Multigene Family; Hydrazines; Biological Products
PubMed: 37235858
DOI: 10.1021/acs.orglett.3c01229