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Bioorganic & Medicinal Chemistry Letters Oct 2021Two distinct diazo precursors, imidazotetrazine and nitrous amide, were explored as promoieties in designing prodrugs of 6-diazo-5-oxo-l-norleucine (DON), a glutamine...
Two distinct diazo precursors, imidazotetrazine and nitrous amide, were explored as promoieties in designing prodrugs of 6-diazo-5-oxo-l-norleucine (DON), a glutamine antagonist. As a model for an imidazotetrazine-based prodrug, we synthesized (S)-2-acetamido-6-(8-carbamoyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)-5-oxohexanoic acid (4) containing the entire scaffold of temozolomide, a precursor of the DNA-methylating agent clinically approved for the treatment of glioblastoma multiforme. For a nitrous amide-based prodrug, we synthesized 2-acetamido-6-(((benzyloxy)carbonyl)(nitroso)amino)-5-oxohexanoic acid (5) containing a N-nitrosocarbamate group, which can be converted to a diazo moiety via a mechanism similar to that of streptozotocin, a clinically approved diazomethane-releasing drug containing an N-nitrosourea group. Preliminary characterization confirmed formation of N-acetyl DON (6), also known as duazomycin A, from compound 4 in a pH-dependent manner while compound 5 did not exhibit sufficient stability to allow further characterization. Taken together, our model studies suggest that further improvements are needed to translate this prodrug approach into glutamine antagonist-based therapy.
Topics: Diazooxonorleucine; Drug Design; Drug Stability; Glutamine; Molecular Structure; Prodrugs
PubMed: 34400301
DOI: 10.1016/j.bmcl.2021.128321 -
Molecules (Basel, Switzerland) Aug 2022Cancer cells change their glucose and glutamine (GLU) metabolism to obtain the energy required to continue growing. Glutaminase (GLS) plays a crucial role in promoting...
Cancer cells change their glucose and glutamine (GLU) metabolism to obtain the energy required to continue growing. Glutaminase (GLS) plays a crucial role in promoting cell metabolism for cancer cell growth; targeting GLU metabolism by inhibiting GLS has attracted interest as a potential cancer management strategy. Herein, we employed a sequential screening of traditional Chinese medicine (TCM) database followed by drug-likeness and molecular dynamics simulations against the active site of GLS. We report 12 potent compounds after screening the TCM database against GLS, followed by a drug-likeness filter with Lipinski and Veber rule criteria. Among them, ZINC03978829 and ZINC32296657 were found to have higher binding energy (BE) values than the control compound 6-Diazo-5-Oxo-L-Norleucine, with BEs of -9.3 and -9.7 kcal/mol, respectively, compared to the BE of 6-Diazo-5-Oxo-L-Norleucine (-4.7 kcal/mol) with GLS. Molecular dynamics simulations were used to evaluate the results further, and a 100 ns MD simulation revealed that the hits form stable complexes with GLS and formed 2-5 hydrogen bond interactions. This study indicates that these hits might be employed as GLS inhibitors in the battle against cancer. However, more laboratory tests are a prerequisite to optimize them as GLS inhibitors.
Topics: Diazooxonorleucine; Early Detection of Cancer; Glutaminase; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Neoplasms; Neoplastic Processes
PubMed: 35956989
DOI: 10.3390/molecules27155042 -
Angewandte Chemie (International Ed. in... Apr 2021DON (6-diazo-5-oxo-l-norleucine), a diazo-containing amino acid, has been studied for more than 60 years as a potent antitumor agent, but its biosynthesis has not been...
DON (6-diazo-5-oxo-l-norleucine), a diazo-containing amino acid, has been studied for more than 60 years as a potent antitumor agent, but its biosynthesis has not been elucidated. Here we reveal the complete biosynthetic pathway of alazopeptin, the tripeptide Ala-DON-DON, which has antitumor activity, by gene inactivation and in vitro analysis of recombinant enzymes. We also established heterologous production of N-acetyl-DON in Streptomyces albus. DON is synthesized from lysine by three enzymes and converted to alazopeptin by five enzymes and one carrier protein. Most interestingly, transmembrane protein AzpL was indicated to catalyze diazotization using 5-oxolysine and nitrous acid as substrates. Site-directed mutagenesis of AzpL indicated that the hydroxy group of Tyr-93 is important for the diazotization. These findings expand our knowledge of the enzymology of N-N bond formation.
Topics: Alanine; Diazooxonorleucine; Dipeptides; Molecular Structure; Streptomyces
PubMed: 33624374
DOI: 10.1002/anie.202100462 -
Methods in Molecular Biology (Clifton,... 2021Colon cancer is a highly anabolic entity with upregulation of glycolysis, glutaminolysis, and de novo synthesis of fatty acids, which also induces a hypercatabolic state...
Colon cancer is a highly anabolic entity with upregulation of glycolysis, glutaminolysis, and de novo synthesis of fatty acids, which also induces a hypercatabolic state in the patient. The blockade of either cancer anabolism or host catabolism has been previously proven to be a successful anticancer experimental treatment. However, it is still unclear whether the simultaneous blockade of both metabolic counterparts can limit malignant survival and the energetic consequences of such an approach. In this chapter, by using the CT26.WT murine colon adenocarcinoma cell line as a model of study, we provide a method to simultaneously perform a pharmacological blockade of tumor anabolism and host catabolism, as a feasible therapeutic approach to treat cancer, and to limit its energetic supply.
Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Colonic Neoplasms; Diazooxonorleucine; Drug Screening Assays, Antitumor; Fatty Acid Synthase, Type I; Fatty Acids; Female; Glutaminase; Glutamine; Glycolysis; Hexokinase; Indazoles; Mice; Mice, Inbred BALB C; Molecular Targeted Therapy; Orlistat; Smegmamorpha
PubMed: 32813244
DOI: 10.1007/978-1-0716-0759-6_5 -
Reproduction (Cambridge, England) Dec 2019The developmental competence of in vitro-matured oocytes is still lower than that of the in vivo-matured oocytes due to precocious meiotic resumption and inappropriate...
The developmental competence of in vitro-matured oocytes is still lower than that of the in vivo-matured oocytes due to precocious meiotic resumption and inappropriate cytoplasmic maturation. Although numerous efforts have been attempted to accomplish better in vitro maturation (IVM) condition, only limited progress has been achieved. Thus, a current study was conducted to examine the effects of 6-diazo-5-oxo-l-norleucine (DON, an inhibitor of hyaluronan synthesis) during the first half period of IVM on nuclear/cytoplasmic maturation of porcine oocytes and subsequent embryonic development. Based on the observation of the nucleus pattern, metaphase II (MII) oocyte production rate in 1 µM DON group was significantly higher than other groups at 44 h of IVM. The 1 µM of DON was suggested to be optimal for porcine IVM and was therefore used for further investigation. Meiotic arrest effect of DON was maximal at 6 h of IVM, which was supported by the maintenance of significantly higher intra-oocyte cAMP level. In addition, increased pERK1/2 levels and clear rearrangement of cortical granules in membrane of MII oocytes matured with DON provided the evidence for balanced meiosis progression between nuclear and cytoplasmic maturation. Subsequently, DON significantly improved blastocyst formation rate, total cell numbers, and cellular survival in blastocysts after parthenogenetic activation, in vitro fertilization, and somatic cell nuclear transfer. Altogether, our results showed for the first time that 1 µM DON can be used to increase the yield of developmentally competent MII oocytes by synchronizing nuclear/cytoplasmic maturation, and it subsequently improves embryo developmental competence.
Topics: Animals; Antibiotics, Antineoplastic; Cell Nucleus; Cytoplasm; Diazooxonorleucine; Embryonic Development; Female; Fertilization in Vitro; In Vitro Oocyte Maturation Techniques; Meiosis; Nuclear Transfer Techniques; Oocytes; Pregnancy; Swine
PubMed: 31652418
DOI: 10.1530/REP-19-0235 -
Frontiers in Public Health 2023The global impact of Coronavirus Disease 2019 (COVID-19) has been profound, affecting public health, the global economy, and overall human life. Past experiences with...
BACKGROUND
The global impact of Coronavirus Disease 2019 (COVID-19) has been profound, affecting public health, the global economy, and overall human life. Past experiences with global pandemics underscored the significance of understanding the perception of HCWs and hospital staff in developing and implementing preventive measures. The World Health Organization (WHO) provided protocols to manage the spread of COVID-19 and assist healthcare workers and health systems globally in maintaining high-quality health services.
OBJECTIVE
This study aims to assess nurses' perception, awareness, and compliance regarding the implementation of COVID-19 protocols and explore factors influencing their perception.
METHODOLOGY
A quantitative cross-sectional survey-based study was conducted, distributing a constructed survey among nurses in the Eastern Province of Saudi Arabia.
RESULTS
Out of 141 participants, most adhered to protocols such as hand sanitization, social distancing, and proper personal protective equipment (PPE) usage. The predominant age group among respondents was 31 to 40 years ( = 71, 50%). A significant portion of participants reported holding a bachelor's degree ( = 86, 61%), with only 14% possessing advanced degrees ( = 19). Nearly a third of the nurses in the study had accumulated 6 to 10 years of professional experience ( = 49, 34.8%). A noteworthy percentage of nurses were engaged in daily shifts exceeding 8 h ( = 98, 70%). Gender differences were observed, with females exhibiting a higher tendency to avoid shaking hands and social gatherings. Saudi nationals were more inclined to shake hands and engage in gatherings. Non-Saudi nurses and those aged between <25 to 40 years demonstrated proper donning/doffing practices. Nurses with over 6 years of experience avoided social gatherings, while those working >8 h adhered better to PPE usage, proper donning/doffing, and disposal of PPE in designated bins.
CONCLUSION
Understanding COVID-19 protocols is crucial for tailoring interventions and ensuring effective compliance with COVID-19 preventive measures among nurses. More efforts should be made toward preparing the healthcare nursing to deal with the outbreak. Preparing healthcare nursing with the right knowledge, attitude, and precautionary practices during the COVID-19 outbreak is very essential to patient and public safety.
Topics: Female; Humans; Adult; Saudi Arabia; Cross-Sectional Studies; COVID-19; Diazooxonorleucine; Perception; Nurses
PubMed: 38249370
DOI: 10.3389/fpubh.2023.1291261 -
Nature Reviews. Drug Discovery Dec 2015
Topics: Animals; Antimalarials; Diazooxonorleucine; Glutamine; Malaria, Cerebral; Malaria, Falciparum
PubMed: 26585535
DOI: 10.1038/nrd4786 -
Virology Aug 2017Infection of weanling C57BL/6 mice with the TE strain of Sindbis virus (SINV) causes nonfatal encephalomyelitis associated with hippocampal-based memory impairment that...
Infection of weanling C57BL/6 mice with the TE strain of Sindbis virus (SINV) causes nonfatal encephalomyelitis associated with hippocampal-based memory impairment that is partially prevented by treatment with 6-diazo-5-oxo-l-norleucine (DON), a glutamine antagonist (Potter et al., J Neurovirol 21:159, 2015). To determine the mechanism(s) of protection, lymph node and central nervous system (CNS) tissues from SINV-infected mice treated daily for 1 week with low (0.3mg/kg) or high (0.6mg/kg) dose DON were examined. DON treatment suppressed lymphocyte proliferation in cervical lymph nodes resulting in reduced CNS immune cell infiltration, inflammation, and cell death compared to untreated SINV-infected mice. Production of SINV-specific antibody and interferon-gamma were also impaired by DON treatment with a delay in virus clearance. Cessation of treatment allowed activation of the antiviral immune response and viral clearance, but revived CNS pathology, demonstrating the ability of the immune response to mediate both CNS damage and virus clearance.
Topics: Alphavirus Infections; Animals; Antiviral Agents; Diazooxonorleucine; Encephalomyelitis; Glutamine; Humans; Interferon-gamma; Male; Mice; Mice, Inbred C57BL; Sindbis Virus
PubMed: 28531865
DOI: 10.1016/j.virol.2017.05.013 -
Oncotarget Sep 2015Cancer cells exhibit altered metabolism including aerobic glycolysis that channels several glycolytic intermediates into de novo purine biosynthetic pathway. We...
Cancer cells exhibit altered metabolism including aerobic glycolysis that channels several glycolytic intermediates into de novo purine biosynthetic pathway. We discovered increased expression of phosphoribosyl amidotransferase (PPAT) and phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) enzymes of de novo purine biosynthetic pathway in lung adenocarcinomas. Transcript analyses from next-generation RNA sequencing and gene expression profiling studies suggested that PPAT and PAICS can serve as prognostic biomarkers for aggressive lung adenocarcinoma. Immunohistochemical analysis of PAICS performed on tissue microarrays showed increased expression with disease progression and was significantly associated with poor prognosis. Through gene knockdown and over-expression studies we demonstrate that altering PPAT and PAICS expression modulates pyruvate kinase activity, cell proliferation and invasion. Furthermore we identified genomic amplification and aneuploidy of the divergently transcribed PPAT-PAICS genomic region in a subset of lung cancers. We also present evidence for regulation of both PPAT and PAICS and pyruvate kinase activity by L-glutamine, a co-substrate for PPAT. A glutamine antagonist, 6-Diazo-5-oxo-L-norleucine (DON) blocked glutamine mediated induction of PPAT and PAICS as well as reduced pyruvate kinase activity. In summary, this study reveals the regulatory mechanisms by which purine biosynthetic pathway enzymes PPAT and PAICS, and pyruvate kinase activity is increased and exposes an existing metabolic vulnerability in lung cancer cells that can be explored for pharmacological intervention.
Topics: Adenocarcinoma; Aged; Amidophosphoribosyltransferase; Aneuploidy; Animals; Biomarkers, Tumor; Carboxy-Lyases; Cell Line, Tumor; Cell Proliferation; Chickens; Diazooxonorleucine; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glutamine; Humans; Lung Neoplasms; Male; Mice; Middle Aged; Neoplasm Invasiveness; Neoplasm Transplantation; Oligonucleotide Array Sequence Analysis; Peptide Synthases; Prognosis; Purines
PubMed: 26140362
DOI: 10.18632/oncotarget.4352 -
Frontiers in Immunology 2020Transplant tolerance in the absence of long-term immunosuppression has been an elusive goal for solid organ transplantation. Recently, it has become clear that metabolic...
Transplant tolerance in the absence of long-term immunosuppression has been an elusive goal for solid organ transplantation. Recently, it has become clear that metabolic reprogramming plays a critical role in promoting T cell activation, differentiation, and function. Targeting metabolism can preferentially inhibit T cell effector generation while simultaneously promoting the generation of T regulatory cells. We hypothesized that costimulatory blockade with CTLA4Ig in combination with targeting T cell metabolism might provide a novel platform to promote the induction of transplant tolerance.
Topics: Abatacept; Allografts; Animals; Deoxyglucose; Diazooxonorleucine; Glycolysis; Immunosuppression Therapy; Immunosuppressive Agents; Lymphocyte Activation; Metformin; Mice; T-Lymphocytes; Transplantation Tolerance
PubMed: 32328063
DOI: 10.3389/fimmu.2020.00572