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Journal of the American Chemical Society Sep 2011A fluorescent ribonucleoside alphabet consisting of highly emissive purine ((th)A, (th)G) and pyrimidine ((th)U, (th)C) analogues, all derived from...
A fluorescent ribonucleoside alphabet consisting of highly emissive purine ((th)A, (th)G) and pyrimidine ((th)U, (th)C) analogues, all derived from thieno[3,4-d]pyrimidine as the heterocyclic nucleus, is described. Structural and biophysical analyses demonstrated that the emissive analogues are faithful isomorphic nucleoside surrogates. Photophysical analysis established that the nucleosides offer highly desirable qualities, including visible emission, high quantum yield, and responsiveness to environmental perturbations, traits entirely lacking in their native counterparts.
Topics: Crystallography, X-Ray; Fluorescence; Models, Molecular; Molecular Conformation; Pyrimidines; RNA; Stereoisomerism
PubMed: 21866967
DOI: 10.1021/ja206095a -
Advances in Pharmacology (San Diego,... 2011Among the purine and pyrimidine receptors, the discovery of small molecular allosteric modulators has been most highly advanced for the A(1) and A(3) adenosine receptors... (Review)
Review
Among the purine and pyrimidine receptors, the discovery of small molecular allosteric modulators has been most highly advanced for the A(1) and A(3) adenosine receptors (ARs). These AR modulators have allosteric effects that are structurally separated from the orthosteric effects in SAR studies. The benzoylthiophene derivatives tend to act as allosteric agonists as well as selective positive allosteric modulators (PAMs) of the A(1) AR. A 2-amino-3-aroylthiophene derivative T-62 has been under development as a PAM of the A(1) AR for the treatment of chronic pain. Several structurally distinct classes of allosteric modulators of the human A(3) AR have been reported: 3-(2-pyridinyl)isoquinolines, 2,4-disubstituted quinolines, 1H-imidazo-[4,5-c]quinolin-4-amines, endocannabinoid 2-arachidonylglycerol, and the food dye Brilliant Black BN. Site-directed mutagenesis of A(1) and A(3) ARs has identified residues associated with the allosteric effect, distinct from those that affect orthosteric binding. A few small molecular allosteric modulators have been reported for several of the P2X ligand-gated ion channels and the G protein-coupled P2Y receptor nucleotides. Metal ion modulation of the P2X receptors has been extensively explored. The allosteric approach to modulation of purine and pyrimidine receptors looks promising for development of drugs that are event and site specific in action.
Topics: Allosteric Regulation; Animals; Humans; Nucleotides; Pyrimidines; Receptors, Purinergic; Receptors, Purinergic P1
PubMed: 21586360
DOI: 10.1016/B978-0-12-385526-8.00007-2 -
Cells Feb 2022Nucleotides are synthesized through two distinct pathways: de novo synthesis and nucleoside salvage. Whereas the de novo pathway synthesizes nucleotides from amino acids... (Review)
Review
Nucleotides are synthesized through two distinct pathways: de novo synthesis and nucleoside salvage. Whereas the de novo pathway synthesizes nucleotides from amino acids and glucose, the salvage pathway recovers nucleosides or bases formed during DNA or RNA degradation. In contrast to high proliferating non-malignant cells, which are highly dependent on the de novo synthesis, cancer cells can switch to the nucleoside salvage pathways to maintain efficient DNA replication. Pyrimidine de novo synthesis remains the target of interest in cancer therapy and several inhibitors showed promising results in cancer cells and in vivo models. In the 1980s and 1990s, poor responses were however observed in clinical trials with several of the currently existing pyrimidine synthesis inhibitors. To overcome the observed limitations in clinical trials, targeting pyrimidine salvage alone or in combination with pyrimidine de novo inhibitors was suggested. Even though this approach showed initially promising results, it received fresh attention only recently. Here we discuss the re-discovery of targeting pyrimidine salvage pathways for DNA replication alone or in combination with inhibitors of pyrimidine de novo synthesis to overcome limitations of commonly used antimetabolites in various preclinical cancer models and clinical trials. We also highlight newly emerged targets in pyrimidine synthesis as well as pyrimidine salvage as a promising target in immunotherapy.
Topics: Neoplasms; Nucleosides; Nucleotides; Pyrimidines
PubMed: 35203388
DOI: 10.3390/cells11040739 -
Molecules (Basel, Switzerland) May 2021Pyrazolo[1,5-]pyrimidine () derivatives are an enormous family of -heterocyclic compounds that possess a high impact in medicinal chemistry and have attracted a great... (Review)
Review
Pyrazolo[1,5-]pyrimidine () derivatives are an enormous family of -heterocyclic compounds that possess a high impact in medicinal chemistry and have attracted a great deal of attention in material science recently due to their significant photophysical properties. Consequently, various researchers have developed different synthesis pathways for the preparation and post-functionalization of this functional scaffold. These transformations improve the structural diversity and allow a synergic effect between new synthetic routes and the possible applications of these compounds. This contribution focuses on an overview of the current advances (2015-2021) in the synthesis and functionalization of diverse pyrazolo[1,5-]pyrimidines. Moreover, the discussion highlights their anticancer potential and enzymatic inhibitory activity, which hopefully could lead to new rational and efficient designs of drugs bearing the pyrazolo[1,5-]pyrimidine core.
Topics: Animals; Antineoplastic Agents; Catalysis; Enzyme Inhibitors; Humans; Pyrazoles; Pyrimidines
PubMed: 34063043
DOI: 10.3390/molecules26092708 -
Plant Physiology Jan 2020Nucleotide metabolism is an essential function in plants.
Nucleotide metabolism is an essential function in plants.
Topics: Models, Biological; Nucleotides; Plants; Purines; Pyrimidines
PubMed: 31641078
DOI: 10.1104/pp.19.00955 -
Annual Review of Biochemistry 2009Thiamin is synthesized by most prokaryotes and by eukaryotes such as yeast and plants. In all cases, the thiazole and pyrimidine moieties are synthesized in separate... (Review)
Review
Thiamin is synthesized by most prokaryotes and by eukaryotes such as yeast and plants. In all cases, the thiazole and pyrimidine moieties are synthesized in separate branches of the pathway and coupled to form thiamin phosphate. A final phosphorylation gives thiamin pyrophosphate, the active form of the cofactor. Over the past decade or so, biochemical and structural studies have elucidated most of the details of the thiamin biosynthetic pathway in bacteria. Formation of the thiazole requires six gene products, and formation of the pyrimidine requires two. In contrast, details of the thiamin biosynthetic pathway in yeast are only just beginning to emerge. Only one gene product is required for the biosynthesis of the thiazole and one for the biosynthesis of the pyrimidine. Thiamin can also be transported into the cell and can be salvaged through several routes. In addition, two thiamin degrading enzymes have been characterized, one of which is linked to a novel salvage pathway.
Topics: Animals; Eukaryotic Cells; Fungi; Humans; Plants; Prokaryotic Cells; Pyrimidines; Thiamine; Thiazoles
PubMed: 19348578
DOI: 10.1146/annurev.biochem.78.072407.102340 -
International Journal For Parasitology Mar 2004Toxoplasma gondii is an obligate intracellular protozoan parasite which is a significant human and veterinary pathogen. Other members of the phylum Apicomplexa are also... (Review)
Review
Toxoplasma gondii is an obligate intracellular protozoan parasite which is a significant human and veterinary pathogen. Other members of the phylum Apicomplexa are also important pathogens including Plasmodium species (i.e. malaria), Eimeria species, Neospora, Babesia, Theileria and Cryptosporidium. Unlike most of these organisms, T. gondii is readily amenable to genetic manipulation in the laboratory. Cell biology studies are more readily performed in T. gondii due to the high efficiency of transient and stable transfection, the availability of many cell markers, and the relative ease with which the parasite can be studied using advanced microscopic techniques. Thus, for many experimental questions, T. gondii remains the best model system to study the biology of the Apicomplexa. Our understanding of the mechanisms of drug resistance, the biology of the apicoplast, and the process of host cell invasion has been advanced by studies in T. gondii. Heterologous expression of apicomplexan proteins in T. gondii has frequently facilitated further characterisation of proteins that could not be easily studied. Recent studies of Apicomplexa have been complemented by genome sequencing projects that have facilitated discovery of surprising differences in cell biology and metabolism between Apicomplexa. While results in T. gondii will not always be applicable to other Apicomplexa, T. gondii remains an important model system for understanding the biology of apicomplexan parasites.
Topics: Animals; Antiprotozoal Agents; Genes, Protozoan; Models, Biological; Purines; Pyrimidines; Toxoplasma
PubMed: 15003501
DOI: 10.1016/j.ijpara.2003.12.009 -
Microbial Cell Factories May 2014The complete sequencing and annotation of the genomes of industrially-important Bacillus species has enhanced our understanding of their properties, and allowed advances... (Review)
Review
The complete sequencing and annotation of the genomes of industrially-important Bacillus species has enhanced our understanding of their properties, and allowed advances in genetic manipulations in other Bacillus species. Post-genomic studies require simple and highly efficient tools to enable genetic manipulation. Here, we summarize the recent progress in genetic engineering strategies for Bacillus species. We review the available genetic tools that have been developed in Bacillus species, as well as methods developed in other species that may also be applicable in Bacillus. Furthermore, we address the limitations and challenges of the existing methods, and discuss the future research prospects in developing novel and useful tools for genetic modification of Bacillus species.
Topics: Bacillus; Bacterial Proteins; Genetic Engineering; Integrases; Orotate Phosphoribosyltransferase; Pentosyltransferases; Pyrimidines; Recombination, Genetic; Repressor Proteins; Viral Regulatory and Accessory Proteins
PubMed: 24885003
DOI: 10.1186/1475-2859-13-63 -
International Journal of Molecular... Sep 2021CAD (Carbamoyl-phosphate synthetase 2, Aspartate transcarbamoylase, and Dihydroorotase) is a multifunctional protein that participates in the initial three... (Review)
Review
CAD (Carbamoyl-phosphate synthetase 2, Aspartate transcarbamoylase, and Dihydroorotase) is a multifunctional protein that participates in the initial three speed-limiting steps of pyrimidine nucleotide synthesis. Over the past two decades, extensive investigations have been conducted to unmask CAD as a central player for the synthesis of nucleic acids, active intermediates, and cell membranes. Meanwhile, the important role of CAD in various physiopathological processes has also been emphasized. Deregulation of CAD-related pathways or CAD mutations cause cancer, neurological disorders, and inherited metabolic diseases. Here, we review the structure, function, and regulation of CAD in mammalian physiology as well as human diseases, and provide insights into the potential to target CAD in future clinical applications.
Topics: Animals; Aspartate Carbamoyltransferase; Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing); Dihydroorotase; Humans; Mammals; Pyrimidines
PubMed: 34638594
DOI: 10.3390/ijms221910253 -
Molecules (Basel, Switzerland) Dec 20222,4-Diaminopyrimidines and (dialkylamino)azabicyclo-nonanes possess activity against protozoan parasites. A series of fused hybrids were synthesized and tested in vitro...
2,4-Diaminopyrimidines and (dialkylamino)azabicyclo-nonanes possess activity against protozoan parasites. A series of fused hybrids were synthesized and tested in vitro against pathogens of malaria tropica and sleeping sickness. The activities and selectivities of compounds strongly depended on the substitution pattern of both ring systems as well as on the position of the nitrogen atom in the bicycles. The most promising hybrids of 3-azabicyclo-nonane with 2-aminopyrimidine showed activity against NF54 in submicromolar concentration and high selectivity. A hybrid with pyrrolidino substitution of the 2-azabicyclo-nonane as well as of the pyrimidine moiety exhibited promising activity against the multiresistant K1 strain of . A couple of hybrids of 2-azabicyclo-nonanes with 2-(dialkylamino)pyrimidines possessed high activity against STIB900 and good selectivity.
Topics: Humans; Plasmodium falciparum; Antiprotozoal Agents; Trypanosoma brucei rhodesiense; Pyrimidines; Malaria, Falciparum; Parasitic Sensitivity Tests; Structure-Activity Relationship
PubMed: 36615504
DOI: 10.3390/molecules28010307