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Bioorganic & Medicinal Chemistry Mar 2021Kinetin (N-furfuryladenine), a plant growth substance of the cytokinin family, has been shown to modulate aging and various age-related conditions in animal models. Here...
Kinetin (N-furfuryladenine), a plant growth substance of the cytokinin family, has been shown to modulate aging and various age-related conditions in animal models. Here we report the synthesis of kinetin isosteres with the purine ring replaced by other bicyclic heterocycles, and the biological evaluation of their activity in several in vitro models related to neurodegenerative diseases. Our findings indicate that kinetin isosteres protect Friedreich́s ataxia patient-derived fibroblasts against glutathione depletion, protect neuron-like SH-SY5Y cells from glutamate-induced oxidative damage, and correct aberrant splicing of the ELP1 gene in fibroblasts derived from a familial dysautonomia patient. Although the mechanism of action of kinetin derivatives remains unclear, our data suggest that the cytoprotective activity of some purine isosteres is mediated by their ability to reduce oxidative stress. Further, the studies of permeation across artificial membrane and model gut and blood-brain barriers indicate that the compounds are orally available and can reach central nervous system. Overall, our data demonstrate that isosteric replacement of the kinetin purine scaffold is a fruitful strategy for improving known biological activities of kinetin and discovering novel therapeutic opportunities.
Topics: Cell Survival; Cells, Cultured; Cytoprotection; Dose-Response Relationship, Drug; Humans; Kinetin; Molecular Structure; Oxidative Stress; Purines; Structure-Activity Relationship
PubMed: 33497938
DOI: 10.1016/j.bmc.2021.115993 -
Nucleosides, Nucleotides & Nucleic Acids 2020SUMMARYIn June 2019, the Purine and Pyrimidine Society (PPS) organized the 18 biennial symposium on Purine and Pyrimidine Metabolism at the International Agency for...
SUMMARYIn June 2019, the Purine and Pyrimidine Society (PPS) organized the 18 biennial symposium on Purine and Pyrimidine Metabolism at the International Agency for Research on Cancer in Lyon, France. This meeting went over 3 days and gathered students and researchers working in various specialties such as inborn errors, hyper- and hypouricemia and gout, cancer, enzymology, and cardiovascular diseases to exchange and discuss recent advances in the field of purine and pyrimidine metabolism. Here, we give an overview of oral presentations given during the symposium.
Topics: Disease; Humans; Purines; Pyrimidines
PubMed: 32182157
DOI: 10.1080/15257770.2020.1730891 -
Medicinal Research Reviews Sep 2020Purines and pyrimidines are essential nutrients for any cell. Most organisms are able to synthesize their own purines and pyrimidines, but this ability was lost in... (Review)
Review
Purines and pyrimidines are essential nutrients for any cell. Most organisms are able to synthesize their own purines and pyrimidines, but this ability was lost in protozoans that adapted to parasitism, leading to a great diversification in transporter activities in these organisms, especially for the acquisition of amino acids and nucleosides from their hosts throughout their life cycles. Many of these transporters have been shown to have sufficiently different substrate affinities from mammalian transporters, making them good carriers for therapeutic agents. In this review, we summarize the knowledge obtained on purine and pyrimidine activities identified in protozoan parasites to date and discuss their importance for the survival of these parasites and as drug carriers, as well as the perspectives of developments in the field.
Topics: Animals; Protozoan Proteins; Purines; Pyrimidines
PubMed: 32144812
DOI: 10.1002/med.21667 -
Recent Patents on Anti-cancer Drug... 2015Protein kinases constitute one of the largest and most functionally diverse gene families that regulate key cell functions. In past several years, kinase inhibition has... (Review)
Review
Protein kinases constitute one of the largest and most functionally diverse gene families that regulate key cell functions. In past several years, kinase inhibition has emerged as potential anti-cancer drug target. Purine is a priveleged heterocyclic nucleus which exists in the chemical architecture of various bioactive compounds. Numerous reports on the use of purine analogues in the treatment of acute leukemias (thiopurines, pentostatin), as antiviral (acyclovir, penciclovir, ganciclovir), as immunosuppressive (azathioprine), as antitumor (vidarabine), as bronchodilator (theophylline) have been revealed. In the past decade, purine analogues have emerged as significantly potent kinase inhibitors. A fair amount of research has been done and several patents have also been published highlighting the kinase inhibitory action of purines. Caffeine, 2-aminopurine, purvalanol-A, seleciclib, FSBA, adenosine thiol analogue possessing purine as the basic moiety fall under this category. In view of the use of purines for the inhibition of kinases, there is need for compilation of data specifying the prominence of purines in the treatment of cancer through this mechanism. The structure of the potent compounds, their IC50 values, models used and the enzymes/ receptors/ targets involved have been presented in this review. The present compilation covers the patents published entailing the purines as kinase inhibitors and the purine drugs employed in chemotherapy.
Topics: Antineoplastic Agents; Humans; Leukemia; Protein Kinase Inhibitors; Purines; Structure-Activity Relationship
PubMed: 26081925
DOI: 10.2174/1574892810666150617112230 -
International Journal of Molecular... Apr 2023Purines, such as adenine and guanine, perform several important functions in the cell. They are found in nucleic acids; are structural components of some coenzymes,... (Review)
Review
Purines, such as adenine and guanine, perform several important functions in the cell. They are found in nucleic acids; are structural components of some coenzymes, including NADH and coenzyme A; and have a crucial role in the modulation of energy metabolism and signal transduction. Moreover, purines have been shown to play an important role in the physiology of platelets, muscles, and neurotransmission. All cells require a balanced number of purines for growth, proliferation, and survival. Under physiological conditions, enzymes involved in purines metabolism maintain a balanced ratio between their synthesis and degradation in the cell. In humans, the final product of purine catabolism is uric acid, while most other mammals possess the enzyme uricase that converts uric acid to allantoin, which can be easily eliminated with urine. During the last decades, hyperuricemia has been associated with a number of human extra-articular diseases (in particular, the cardiovascular ones) and their clinical severity. In this review, we go through the methods of investigation of purine metabolism dysfunctions, looking at the functionality of xanthine oxidoreductase and the formation of catabolites in urine and saliva. Finally, we discuss how these molecules can be used as markers of oxidative stress.
Topics: Animals; Humans; Uric Acid; Purines; Adenine; Guanine; Xanthine Dehydrogenase; Mammals
PubMed: 37108190
DOI: 10.3390/ijms24087027 -
Nature Metabolism Nov 2021Mammalian cells require activated folates to generate nucleotides for growth and division. The most abundant circulating folate species is 5-methyl tetrahydrofolate...
Mammalian cells require activated folates to generate nucleotides for growth and division. The most abundant circulating folate species is 5-methyl tetrahydrofolate (5-methyl-THF), which is used to synthesize methionine from homocysteine via the cobalamin-dependent enzyme methionine synthase (MTR). Cobalamin deficiency traps folates as 5-methyl-THF. Here, we show using isotope tracing that MTR is only a minor source of methionine in cell culture, tissues or xenografted tumours. Instead, MTR is required for cells to avoid folate trapping and assimilate 5-methyl-THF into other folate species. Under conditions of physiological extracellular folates, genetic MTR knockout in tumour cells leads to folate trapping, purine synthesis stalling, nucleotide depletion and impaired growth in cell culture and as xenografts. These defects are rescued by free folate but not one-carbon unit supplementation. Thus, MTR plays a crucial role in liberating THF for use in one-carbon metabolism.
Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Cell Line, Tumor; Cell Proliferation; Folic Acid; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Metabolic Networks and Pathways; Methionine; Methylation; Mutation; Neoplasms; Purines; Tetrahydrofolates; Vitamin B 12 Deficiency
PubMed: 34799699
DOI: 10.1038/s42255-021-00465-w -
Chemical & Pharmaceutical Bulletin 2018In this review, we have summarized the research effort into the development of unnatural base pairs beyond standard Watson-Crick (WC) base pairs for synthetic biology.... (Review)
Review
In this review, we have summarized the research effort into the development of unnatural base pairs beyond standard Watson-Crick (WC) base pairs for synthetic biology. Prior to introducing our research results, we present investigations by four outstanding groups in the field. Their research results demonstrate the importance of shape complementarity and stacking ability as well as hydrogen-bonding (H-bonding) patterns for unnatural base pairs. On the basis of this research background, we developed unnatural base pairs consisting of imidazo[5',4':4.5]pyrido[2,3-d]pyrimidines and 1,8-naphthyridines, i.e., Im : Na pairs. Since Im bases are recognized as ring-expanded purines and Na bases are recognized as ring-expanded pyrimidines, Im : Na pairs are expected to satisfy the criteria of shape complementarity and enhanced stacking ability. In addition, these pairs have four non-canonical H-bonds. Because of these preferable properties, ImN : NaO, one of the Im : Na pairs, is recognized as a complementary base pair in not only single nucleotide insertion, but also the PCR.
Topics: Base Pairing; Hydrogen Bonding; Naphthyridines; Physical Phenomena; Purines; Pyrimidines; Synthetic Biology
PubMed: 29386463
DOI: 10.1248/cpb.c17-00685 -
Cell Chemical Biology Jul 2023Elevated bloodstream levels of uric acid, a mammalian purine degradation product, are associated with several noncommunicable diseases. Recent studies by Kasahara...
Elevated bloodstream levels of uric acid, a mammalian purine degradation product, are associated with several noncommunicable diseases. Recent studies by Kasahara et al. and Liu et al. define purine-degrading activities of the gut microbiota that lower bloodstream uric acid in atherosclerosis and gout disease models, establishing a novel microbial role in host health.
Topics: Animals; Gastrointestinal Microbiome; Gout; Mammals; Purines; Uric Acid
PubMed: 37478828
DOI: 10.1016/j.chembiol.2023.06.022 -
Cells Sep 2023Purines are required for fundamental biological processes and alterations in their metabolism lead to severe genetic diseases associated with developmental defects whose...
Purines are required for fundamental biological processes and alterations in their metabolism lead to severe genetic diseases associated with developmental defects whose etiology remains unclear. Here, we studied the developmental requirements for purine metabolism using the amphibian as a vertebrate model. We provide the first functional characterization of purine pathway genes and show that these genes are mainly expressed in nervous and muscular embryonic tissues. Morphants were generated to decipher the functions of these genes, with a focus on the adenylosuccinate lyase (), which is an enzyme required for both salvage and de novo purine pathways. knockdown led to a severe reduction in the expression of the myogenic regulatory factors (MRFs: Myod1, Myf5 and Myogenin), thus resulting in defects in somite formation and, at later stages, the development and/or migration of both craniofacial and hypaxial muscle progenitors. The reduced expressions of and , which are two genes specific to the salvage and de novo pathways, respectively, resulted in similar alterations. In conclusion, our data show for the first time that de novo and recycling purine pathways are essential for myogenesis and highlight new mechanisms in the regulation of MRF gene expression.
Topics: Animals; Xenopus laevis; Muscle, Skeletal; Purines; Muscle Development
PubMed: 37830593
DOI: 10.3390/cells12192379 -
Free Radical Research Apr 2021Hydroxyl radical (HO) is the most reactive toward DNA among the reactive oxygen species (ROS) generated in aerobic organisms by cellular metabolisms. HO is generated... (Review)
Review
Hydroxyl radical (HO) is the most reactive toward DNA among the reactive oxygen species (ROS) generated in aerobic organisms by cellular metabolisms. HO is generated also by exogenous sources such as ionizing radiations. In this review we focus on the purine DNA damage by HO radicals. In particular, emphasis is given on mechanistic aspects for the various lesion formation and their interconnections. Although the majority of the purine DNA lesions like 8-oxo-purine (8-oxo-Pu) are generated by various ROS (including HO), the formation of 5',8-cyclopurine (cPu) lesions and relies exclusively on the HO attack. Methodologies generally utilized for the purine lesions quantification in biological samples are reported and critically discussed. Recent results on cPu and 8-oxo-Pu lesions quantification in various types of biological specimens associated with the cellular repair efficiency as well as with distinct pathologies are presented, providing some insights on their biological significance.
Topics: DNA Damage; Hydroxyl Radical; Purines; Reactive Oxygen Species
PubMed: 33494618
DOI: 10.1080/10715762.2021.1876855