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Yeast (Chichester, England) Mar 2022Orotic acid (OA) is an intermediate of the pyrimidine biosynthesis with high industrial relevance due to its use as precursor for production of biochemical pyrimidines...
Orotic acid (OA) is an intermediate of the pyrimidine biosynthesis with high industrial relevance due to its use as precursor for production of biochemical pyrimidines or its use as carrier molecule in drug formulations. It can be produced by fermentation of microorganisms with engineered pyrimidine metabolism. In this study, we surprisingly discovered the yeast Yarrowia lipolytica as a powerful producer of OA. The overproduction of OA in the Y. lipolytica strain PO1f was found to be caused by the deletion of the URA3 gene which prevents the irreversible decarboxylation of OA to uridine monophosphate. It was shown that the lack of orotidine-5'-phosphate decarboxylase was the reason for the accumulation of OA inside the cell since a rescue mutant of the URA3 deletion in Y. lipolytica PO1f completely prevented the OA secretion into the medium. In addition, pyrimidine limitation in the cell massively enhanced the OA accumulation followed by secretion due to intense overflow metabolism during bioreactor cultivations. Accordingly, supplementation of the medium with 200 mg/L uracil drastically decreased the OA overproduction by 91%. OA productivity was further enhanced in fed-batch cultivation with glucose and ammonium sulfate feed to a maximal yield of 9.62 ± 0.21 g/L. Y. lipolytica is one of three OA overproducing yeasts described in the literature so far, and in this study, the highest productivity was shown. This work demonstrates the potential of Y. lipolytica as a possible production organism for OA and provides a basis for further metabolic pathway engineering to optimize OA productivity.
Topics: Metabolic Engineering; Orotic Acid; Pyrimidines; Yarrowia
PubMed: 34648204
DOI: 10.1002/yea.3673 -
Molecular Diversity Nov 2013A simple and practical four-step protocol for the parallel synthesis of 7-heteroaryl-pyrazolo[1,5-[Formula: see text]]pyrimidine-3-carboxamides was developed. The...
A simple and practical four-step protocol for the parallel synthesis of 7-heteroaryl-pyrazolo[1,5-[Formula: see text]]pyrimidine-3-carboxamides was developed. The synthesis starts with transformation of commercially available 2-acetylpyridine and acetylpyrazine with [Formula: see text] [Formula: see text]-dimethylformamide dimethylacetal into the corresponding [Formula: see text]-3-(dimethylamino)-1-(heteroaryl)prop-2-en-1-ones followed by cyclisation with methyl 5-amino-1[Formula: see text]-pyrazole-4-carboxylate to give methyl 7-heteroarylpyrazolo[1,5-[Formula: see text]]pyrimidine-3-carboxylates. Hydrolysis of the ester group and subsequent amidation of the so formed carboxylic acids with 12 primary and secondary aliphatic amines furnished a library of 24 title compounds in good overall yields and purity.
Topics: Combinatorial Chemistry Techniques; Cyclization; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Pyrazoles; Pyrimidines
PubMed: 23975596
DOI: 10.1007/s11030-013-9469-3 -
Nucleosides, Nucleotides & Nucleic Acids 2021Pyrimidine antimetabolic agents are the essential drugs in treatment of various tumors. Novel synthesis and biological evaluation of the pyrimidine derivatives...
Pyrimidine antimetabolic agents are the essential drugs in treatment of various tumors. Novel synthesis and biological evaluation of the pyrimidine derivatives incorporating selenium element and amino acid carrier as potential antitumor agents have not been tried and studied. Based on the biological significance of pyrimidine structure, these two additional elemental fragments maybe enhance the antitumor effect and reduce toxic side effects of pyrimidine agents. The aim of this paper is to synthesis a series of 4-selenopyrimidine derivatives in order to find more potent lead compounds against cancer. In this study, 12 new 4-selenopyrimidine derivatives that are unstable in acidic solutions but very stable in alkaline and neutral solutions avoiding light were synthesized, and the antitumor activities on HepG2 cell lines of these compounds were evaluated by MTT assay. The results have shown that these compounds could reduce the proliferation of HepG2 cells in a dose-dependent fashion, and the inhibitory activity of compounds a6 was greater than that of positive control 5-fluorouracil (5-FU), the IC for a6 was 3.63 μM. In the comprehensive analysis of the structure-activity relationship, we could draw the antitumor effect of selenouracil derivatives is stronger than those of selenothymine derivatives. These results suggest that the substituent groups of selenium element and amino acid on the pyrimidine derivatives are vital for their antitumor activities on HepG2 cells.
Topics: Antineoplastic Agents; Cell Survival; Chemistry Techniques, Synthetic; Hep G2 Cells; Humans; Hydrogen-Ion Concentration; Pyrimidines
PubMed: 33073661
DOI: 10.1080/15257770.2020.1833342 -
Bioorganic & Medicinal Chemistry Letters Feb 2014We designed and synthesized a novel series of phenylamino- and phenoxy-substituted pyrazolo[3,4-d]pyrimidine derivatives as GPR119 agonists. SAR studies indicated that...
We designed and synthesized a novel series of phenylamino- and phenoxy-substituted pyrazolo[3,4-d]pyrimidine derivatives as GPR119 agonists. SAR studies indicated that electron-withdrawing substituents on the phenyl ring are important for potency and full efficacy. Compound 26 combined good potency with a promising pharmacokinetic profile in mice, and lowered the glucose excursion in mice in an oral glucose-tolerance test.
Topics: Animals; Drug Discovery; Humans; Mice; Pyrazoles; Pyrimidines; Receptors, G-Protein-Coupled; Structure-Activity Relationship
PubMed: 24412066
DOI: 10.1016/j.bmcl.2013.12.063 -
Molecules (Basel, Switzerland) Oct 2019A small and focused library of steroidal non-fused and fused pyrimidines was prepared from pregnenolone acetate and diosgenin, respectively. The key step was the...
A small and focused library of steroidal non-fused and fused pyrimidines was prepared from pregnenolone acetate and diosgenin, respectively. The key step was the cycloaddition reaction of nitrogen-containing 1,3-binucleophiles with the steroidal α,β-unsaturated ketone. Urea, thiourea and guanidine reacted in a similar manner and afforded the steroidal pyrimidines in good yields. The antiproliferative tests against human tumor cell lines gave GI values in the micromolar range and had no effect on healthy fibroblasts. Additional experiments indicated that the compounds did not act as P-glycoprotein substrates, thus avoiding the rise of drug resistance. The fused steroidal pyrimidinethione was selected as drug lead for further testing due to its strong antiproliferative activities within the low micromolar range.
Topics: Acetates; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Neoplasms; Nitrogen; Pregnenolone; Pyrimidines; Steroids; Structure-Activity Relationship
PubMed: 31614780
DOI: 10.3390/molecules24203676 -
Molecular Diversity Nov 2009A general review (138 references) focused on the recent advances in the application of Meldrum's acid reactivity for synthesis of diverse pyridine and pyrimidine... (Review)
Review
A general review (138 references) focused on the recent advances in the application of Meldrum's acid reactivity for synthesis of diverse pyridine and pyrimidine derivatives, mostly small and drug-like molecules is presented.
Topics: Dioxanes; History, 19th Century; History, 20th Century; Pyridines; Pyrimidines
PubMed: 19381852
DOI: 10.1007/s11030-009-9136-x -
Journal of Pharmaceutical and... Jan 2018Two analogs of sildenafil (compounds 1 and 2) were detected in three powder products acquired from online drug markets during an LC-UV-MS analysis of psychotropic drugs....
Two analogs of sildenafil (compounds 1 and 2) were detected in three powder products acquired from online drug markets during an LC-UV-MS analysis of psychotropic drugs. Their structures were established by high-resolution mass spectrometry and NMR spectroscopy. Compound 1 was identified as 5-(5-(3,5-dimethylpiperazine-1-carbonothioyl)-2-ethoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-7(6H)-thione and named dimethyldithiodenafil. Compound 2 was identified as 5-(5-(3,5-dimethylpiperazine-1-carbonothioyl)-2-ethoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one and named dimethylthiocarbodenafil. Compound 1 was subjected to the phosphodiesterase assay (IC=0.20nM). The three powder products were found to contain 12-19mg of dimethyldithiodenafil and 1.4-3.9mg of dimethylthiocarbodenafil per tube.
Topics: Chromatography, Liquid; Magnetic Resonance Spectroscopy; Mass Spectrometry; Phosphodiesterase Inhibitors; Powders; Psychotropic Drugs; Pyrimidines; Sildenafil Citrate
PubMed: 29017110
DOI: 10.1016/j.jpba.2017.09.025 -
Purine and pyrimidine metabolism between millennia: what has been accomplished, what has to be done?Advances in Experimental Medicine and... 2000
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The Journal of Biological Chemistry Oct 1957
Topics: Escherichia coli; Nucleosides; Nucleotides; Pyrimidines; Uracil
PubMed: 13475346
DOI: No ID Found -
Molecules (Basel, Switzerland) Jul 2020A series of novel phenyl methoxyacrylate derivatives containing a 2-alkenylthiopyrimidine substructure were designed, synthesized, and evaluated in terms of acaricidal...
A series of novel phenyl methoxyacrylate derivatives containing a 2-alkenylthiopyrimidine substructure were designed, synthesized, and evaluated in terms of acaricidal activity. The structures of the title compounds were identified by H NMR, C NMR and high-resolution mass spectra (HRMS). Compound ()-methyl 2-(2-((2-(3,3-dichloroallylthio)-6-(trifluoromethyl)pyrimidin-4-yloxy)methyl)phenyl)-3-methoxyacr-ylate () exhibited significant acaricidal activity against () in greenhouse tests possessing nearly twice the larvicidal and ovicidal activity compared to fluacrypyrim. Furthermore, the results of the field trials demonstrated that compound could effectively control with long-lasting persistence and rapid action. The toxicology data in terms of LD value confirmed that compound has a relatively low acute toxicity to mammals, birds, and honeybees.
Topics: Acaricides; Acrylates; Animals; Insecticides; Larva; Molecular Structure; Pyrimidines; Tetranychidae
PubMed: 32722453
DOI: 10.3390/molecules25153379