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IUBMB Life Dec 2019Colorectal cancer (CRC) is one of the most common malignancies in the world. Despite intensive advances in diagnosis and treatment of CRC, it is yet one of the leading... (Review)
Review
Colorectal cancer (CRC) is one of the most common malignancies in the world. Despite intensive advances in diagnosis and treatment of CRC, it is yet one of the leading cause of cancer related morbidity and mortality. Therefore, there is an urgent medical need for alternative therapeutic approaches to treat CRC. The 70 kDa heat shock proteins (Hsp70s) are a family of evolutionary conserved heat shock proteins, which play an important role in cell homeostasis and survival. They overexpress in various types of malignancy including CRC and are typically accompanied with poor prognosis. Hence, inhibition of Hsp70 may be considered as a striking chemotherapeutic avenue. This review summarizes the current knowledge on the progress made so far to discover compounds, which target the Hsp70 family, with particular emphasis on their efficacy in treatment of CRC. We also briefly explain the induction of Hsp70 as a strategy to prevent CRC.
Topics: Antineoplastic Agents; Biological Products; Carbamates; Colorectal Neoplasms; Endoplasmic Reticulum Chaperone BiP; HSP70 Heat-Shock Proteins; Heat-Shock Proteins; Humans; Molecular Targeted Therapy; Purine Nucleosides; Pyrimidinones
PubMed: 31441584
DOI: 10.1002/iub.2157 -
Experimental Eye Research Oct 2014This review highlights recent findings that describ how purines modulate the physiological and pathophysiological responses of ocular tissues. For example, in lacrimal... (Review)
Review
Purines in the eye: recent evidence for the physiological and pathological role of purines in the RPE, retinal neurons, astrocytes, Müller cells, lens, trabecular meshwork, cornea and lacrimal gland.
This review highlights recent findings that describ how purines modulate the physiological and pathophysiological responses of ocular tissues. For example, in lacrimal glands the cross-talk between P2X7 receptors and both M3 muscarinic receptors and α1D-adrenergic receptors can influence tear secretion. In the cornea, purines lead to post-translational modification of EGFR and structural proteins that participate in wound repair in the epithelium and influence the expression of matrix proteins in the stroma. Purines act at receptors on both the trabecular meshwork and ciliary epithelium to modulate intraocular pressure (IOP); ATP-release pathways of inflow and outflow cells differ, possibly permitting differential modulation of adenosine delivery. Modulators of trabecular meshwork cell ATP release include cell volume, stretch, extracellular Ca(2+) concentration, oxidation state, actin remodeling and possibly endogenous cardiotonic steroids. In the lens, osmotic stress leads to ATP release following TRPV4 activation upstream of hemichannel opening. In the anterior eye, diadenosine polyphosphates such as Ap4A act at P2 receptors to modulate the rate and composition of tear secretion, impact corneal wound healing and lower IOP. The Gq11-coupled P2Y1-receptor contributes to volume control in Müller cells and thus the retina. P2X receptors are expressed in neurons in the inner and outer retina and contribute to visual processing as well as the demise of retinal ganglion cells. In RPE cells, the balance between extracellular ATP and adenosine may modulate lysosomal pH and the rate of lipofuscin formation. In optic nerve head astrocytes, mechanosensitive ATP release via pannexin hemichannels, coupled with stretch-dependent upregulation of pannexins, provides a mechanism for ATP signaling in chronic glaucoma. With so many receptors linked to divergent functions throughout the eye, ensuring the transmitters remain local and stimulation is restricted to the intended target may be a key issue in understanding how physiological signaling becomes pathological in ocular disease.
Topics: Animals; Astrocytes; Cornea; Ependymoglial Cells; Eye; Eye Diseases; Humans; Lacrimal Apparatus; Lens, Crystalline; Purine Nucleosides; Purine Nucleotides; Retinal Neurons; Retinal Pigment Epithelium; Signal Transduction; Trabecular Meshwork
PubMed: 25151301
DOI: 10.1016/j.exer.2014.08.009 -
Organic Letters Oct 2010A one-pot synthesis of ethers derived from inosine, guanosine, 2'-deoxyguanosine, and pyrimidinones is described. Exposure of the heterocycle to...
A one-pot synthesis of ethers derived from inosine, guanosine, 2'-deoxyguanosine, and pyrimidinones is described. Exposure of the heterocycle to 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and Cs(2)CO(3) produces a reactive intermediate, which is converted to the desired ether by subsequent addition of an appropriate alcohol or phenol and Cs(2)CO(3). Although rapid formation of HMPA from BOP can occur in the presence of an alcohol and base, as demonstrated by the reaction with methanol, under appropriate conditions these heteroaryl ethers can be efficiently synthesized.
Topics: Ethers; Molecular Structure; Purine Nucleosides; Pyrimidines
PubMed: 20845979
DOI: 10.1021/ol101655h -
Molecules (Basel, Switzerland) Mar 2019Glycosylation of 6-amino-4-methoxy-1H-pyrazolo[3,4-]pyrimidine and its iodo- and bromo- analogues with the protected ribofuranose and 2'-deoxyribofuranose under...
Glycosylation of 6-amino-4-methoxy-1H-pyrazolo[3,4-]pyrimidine and its iodo- and bromo- analogues with the protected ribofuranose and 2'-deoxyribofuranose under different conditions resulted in the synthesis of ⁸- and ⁸-glycosylated purine nucleosides. Five key intermediate nucleosides, having 6-methoxy, 7-iodo, and 2-bromo groups, were further derivatized to 23 final 8-aza-7-deazapurine nucleoside derivatives. The structures of ⁸- and ⁸-glycosylated products were assigned based on UV and NMR spectra. HMBC analysis of 2D NMR spectra and X-ray crystallographic studies of the representative compounds unambiguously verified the connection of ribose ring to ⁸- or ⁸-position of the purine ring. The anticancer activity of these new compounds was evaluated.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Chemistry Techniques, Synthetic; Humans; Models, Molecular; Molecular Conformation; Molecular Structure; Purine Nucleosides; Purines; Spectrum Analysis; Structure-Activity Relationship
PubMed: 30862058
DOI: 10.3390/molecules24050983 -
Microbiology (Reading, England) Jul 2018The methionine salvage pathway (MSP) is critical for regeneration of S-adenosyl-l-methionine (SAM), a widely used cofactor involved in many essential metabolic...
The methionine salvage pathway (MSP) is critical for regeneration of S-adenosyl-l-methionine (SAM), a widely used cofactor involved in many essential metabolic reactions. The MSP has been completely elucidated in aerobic organisms, and found to rely on molecular oxygen. Since anaerobic organisms do not use O2, an alternative pathway(s) must be operating. We sought to evaluate whether the functions of two annotated MSP enzymes from Methanocaldococcus jannaschii, a methylthioinosine phosphorylase (MTIP) and a methylthioribose 1-phosphate isomerase (MTRI), are consistent with functioning in a modified anaerobic MSP (AnMSP). We show here that recombinant MTIP is active with six different purine nucleosides, consistent with its function as a general purine nucleoside phosphorylase for both AnMSP and purine salvage. Recombinant MTRI is active with both 5-methylthioribose 1-phosphate and 5-deoxyribose 1-phosphate as substrates, which are generated from phosphororolysis of 5'-methylthioinosine and 5'-deoxyinosine by MTIP, respectively. Together, these data suggest that MTIP and MTRI may function in a novel pathway for recycling the 5'-deoxyadenosine moiety of SAM in M. jannaschii. These enzymes may also enable biosynthesis of 6-deoxy-5-ketofructose 1-phosphate (DKFP), an essential intermediate in aromatic amino acid biosynthesis. Finally, we utilized a homocysteine auxotrophic strain of Methanosarcina acetivorans Δma1821-22Δoahs (HcyAux) to identify potential AnMSP intermediates in vivo. Growth recovery experiments of the M. acetivorans HcyAux were performed with known and proposed intermediates for the AnMSP. Only one metabolite, 2-keto-(4-methylthio)butyric acid, rescued growth of M. acetivorans HcyAux in the absence of homocysteine. This observation may indicate that AnMSP pathways substantially differ among methanogens from phylogenetically divergent genera.
Topics: Bacterial Proteins; Biosynthetic Pathways; Deoxyadenosines; Fructosephosphates; Gene Expression; Genetic Complementation Test; Kinetics; Methanocaldococcus; Methanosarcina; Methionine; Molecular Weight; Recombinant Proteins; S-Adenosylmethionine; Species Specificity; Substrate Specificity
PubMed: 29877790
DOI: 10.1099/mic.0.000670 -
Nucleosides, Nucleotides & Nucleic Acids May 20099-(2',3'-Dideoxy-2',3'-difluoro-beta-D-arabinofuranosyl)adenine (20), 2-chloro-9-(2',3'-dideoxy-2,3-difluoro-beta-D-arabinofuranosyl)adenine (22), as well as their...
9-(2',3'-Dideoxy-2',3'-difluoro-beta-D-arabinofuranosyl)adenine (20), 2-chloro-9-(2',3'-dideoxy-2,3-difluoro-beta-D-arabinofuranosyl)adenine (22), as well as their respective alpha-anomers 21 and 23, were synthesized by the nucleobase anion glycosylation of intermediate 5-O-benzoyl-2,3-dideoxy-2,3-difluoro-alpha-D-arabinofuranosyl bromide (13) starting from methyl 5-O-benzyl-3-deoxy-3-fluoro-alpha-D-ribofuranoside (3) and methyl 5-O-benzoyl-alpha-D-xylofuranoside (10). These compounds were evaluated as potential inhibitors of HIV-1 and hepatitis C virus in human PBM and Huh-7 Replicon cells, respectively. The adenosine analog 20 demonstrated potent activity against HIV-1 in primary human lymphocytes with no apparent cytotoxicity. Conformation of pentofuranose ring of nucleoside 20 in solution was studied by PSEUROT calculations.
Topics: Antiviral Agents; Cell Culture Techniques; Cell Line; Cell Survival; Fluorine Compounds; HIV Infections; HIV-1; Hepacivirus; Hepatitis C; Humans; Lymphocytes; Molecular Conformation; Purine Nucleosides
PubMed: 20183600
DOI: 10.1080/15257770903053979 -
The Journal of Clinical Investigation Oct 1984Purine nucleosides, which accumulate in adenosine deaminase and purine nucleoside phosphorylase deficiency, are toxic to lymphoid cells. Since adenine nucleosides...
Purine nucleosides, which accumulate in adenosine deaminase and purine nucleoside phosphorylase deficiency, are toxic to lymphoid cells. Since adenine nucleosides inhibit S-adenosylhomocysteine hydrolase, they could potentially decrease intracellular methionine synthesis. To test this hypothesis, we measured methionine synthesis by the use of [14C]formate as a radioactive precursor in cultured human T and B lymphoblasts treated with varying concentrations of purine nucleosides; 2'-deoxycoformycin and 8-aminoguanosine were added to inhibit adenosine deaminase and purine nucleoside phosphorylase, respectively. In the T lymphoblasts methionine synthesis was inhibited approximately 50% by 10 microM of 2'-deoxyadenosine, adenine arabinoside, or 2'-deoxyguanosine. By contrast, in the B lymphoblasts methionine synthesis was considerably less affected by these nucleosides, with 50% inhibition occurring at 100 microM of 2'-deoxyadenosine and adenine arabinoside; 100 microM of 2'-deoxyguanosine yielded less than 10% inhibition. Adenosine and guanosine were considerably less potent inhibitors of methionine synthesis in both the T and B lymphoblasts. An adenosine deaminase-deficient and a purine nucleoside phosphorylase-deficient cell line, both of B cell origin, exhibited sensitivities to the nucleosides similar to those of the normal B cell lines. In both the T and B cell lines homocysteine reversed the methionine synthesis inhibition induced by the adenine nucleosides and guanosine and largely reversed that induced by 2'-deoxyguanosine. Methionine synthesis from homocysteine generates free tetrahydrofolate from 5-methyltetrahydrofolate, the main intracellular storage form of folate. We conclude that purine nucleoside toxicity may be partly mediated through (a) decreased intracellular methionine synthesis, and (b) altered folate metabolism.
Topics: Adenosine; B-Lymphocytes; Cell Line; Deoxyadenosines; Deoxyguanosine; Guanosine; Homocysteine; Humans; Inosine; Lymphocyte Activation; Methionine; Purine Nucleosides; T-Lymphocytes; Vidarabine
PubMed: 6332827
DOI: 10.1172/JCI111536 -
Molecules (Basel, Switzerland) Oct 2013An efficient and facile strategy has been developed for bromination of nucleosides using sodium monobromoisocyanurate (SMBI). Our methodology demonstrates bromination at...
An efficient and facile strategy has been developed for bromination of nucleosides using sodium monobromoisocyanurate (SMBI). Our methodology demonstrates bromination at the C-5 position of pyrimidine nucleosides and the C-8 position of purine nucleosides. Unprotected and also several protected nucleosides were brominated in moderate to high yields following this procedure.
Topics: Dimethylformamide; Halogenation; Purine Nucleosides; Pyrimidine Nucleosides; Solubility; Solvents; Triazines
PubMed: 24132197
DOI: 10.3390/molecules181012740 -
Aging Mar 2024CR6-interacting factor 1 (CRIF1), a multifunctional protein that affects mitochondrial function and cell senescence, plays a regulatory role in heart-related diseases....
BACKGROUND
CR6-interacting factor 1 (CRIF1), a multifunctional protein that affects mitochondrial function and cell senescence, plays a regulatory role in heart-related diseases. However, whether CRIF1 participates in myocardial senescence by regulating mitochondrial function remains unclear.
METHODS
Doxorubicin (DOX)-induced C57BL/6 mice to construct mouse myocardial senescence model, and the myocardial function indicators including lactate dehydrogenase (LDH) and Creatine kinase isoform MB (CK-MB) were assessed. The expression of CRIF1 was detected by western blot. Myocardial pathological changes were examined by transthoracic echocardiography and haematoxylin and eosin (H&E) staining. Cell senescence was detected by SA-β-gal staining. JC-1 staining was used to detect mitochondrial membrane potential. Biochemical kits were used to examine oxidative stress-related factors. Additionally, AC16 cardiomyocytes were treated with DOX to mimic the cellular senescence model . Cell activity was detected by cell counting kit-8 (CCK-8) assay. Co-immunoprecipitation (CO-IP) was used to verify the relationship between CRIF1 and peroxidasin (PXDN).
RESULTS
The CRIF1 expression was significantly decreased in DOX-induced senescent mice and AC16 cells. Overexpression of CRIF1 significantly ameliorated DOX-induced myocardial dysfunction and myocardial senescence. Additionally, CRIF1 overexpression attenuated DOX-induced oxidative stress and myocardial mitochondrial dysfunction. Consistently, CRIF1 overexpression also inhibited DOX-induced oxidative stress and senescence in AC16 cells. Moreover, CRIF1 was verified to bind to PXDN and inhibited PXDN expression. The inhibitory effects of CRIF1 overexpression on DOX-induced oxidative stress and senescence in AC16 cells were partly abolished by PXDN expression.
CONCLUSIONS
CRIF1 plays a protective role against DOX-caused mitochondrial dysfunction and myocardial senescence partly through downregulating PXDN.
Topics: Mice; Animals; Mice, Inbred C57BL; Doxorubicin; Myocardium; Oxidative Stress; Myocytes, Cardiac; Mitochondrial Diseases; Apoptosis; Deoxyribonucleosides; Purine Nucleosides
PubMed: 38517371
DOI: 10.18632/aging.205664 -
Annals of Oncology : Official Journal... 1996The observation of lymphopenia in children deficient in adenosine deaminase (ADA) led to exploration of an inhibitor of the enzyme in lymphoid malignancies; thus... (Review)
Review
The observation of lymphopenia in children deficient in adenosine deaminase (ADA) led to exploration of an inhibitor of the enzyme in lymphoid malignancies; thus deoxycoformycin was the first purine nucleotide used in human trials. Fludarabine and 2-chlorodeoxyadenosine (2-CdA), agents resistant to deamination by ADA, have been utilized in the past decade. All of these drugs act as competitors for deoxyadenosine triphosphate at the A sites of the elongating DNA strand, terminating DNA synthesis. However, their remarkable efficacy in indolent lymphoid malignancies is not well explained by this mechanism of action. The induction of apoptosis and resultant cytotoxicity may be important in their activity. As a single agent, fludarabine has been associated with overall remission rates as high as 55% in previously treated patients and 79% in previously untreated patients. With this agent, a dosage regimen of 25-30 mg/m2 daily over 5 days seems to be the most effective to date. Fludarabine has shown more favorable remission rates than the traditional salvage regimens incorporating anthracyclines and alkylating agents. Regimens combining fludarabine with mitoxantrone and with doxorubicin have shown minimal therapeutic advantage in CLL, while combination with cyclophosphamide appears promising. Remission rates with deoxycoformycin have been lower than with fludarabine, but studies have been small in patient numbers. The agent 2-CdA, first successful in hairy-cell leukemia, has shown overall response rates in chronic lymphocytic leukemia similar to those seen with fludarabine. Whether or not cross-resistance occurs among the purine analogs has not been fully determined, but occasional patients with disease refractory to fludarabine have responded to 2-CdA. Cumulative myelosuppression and immunosuppression may be experienced however. In the B-cell neoplastic entity, Waldenström's macroglobulinemia, fludarabine therapy in patients previously treated with alkylating agents and/or steroids produced a 36% response rate. Only two previously untreated patients received fludarabine, and both responded. A similar response rate of 40% was seen when 2-CdA was administered to previously treated patients. This response rate increased to 85% in a study of 26 previously untreated patients, making this one of the most effective drugs yet investigated in this condition.
Topics: Antineoplastic Agents; Cladribine; Clinical Trials as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Purine Nucleosides; Vidarabine; Waldenstrom Macroglobulinemia
PubMed: 9010576
DOI: 10.1093/annonc/7.suppl_6.s27