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Mini Reviews in Medicinal Chemistry Sep 2007Recently a few new purine nucleoside analogues (PNA) have been synthesized and introduced into preclinical and clinical trials. The transition-state theory has led to... (Review)
Review
Recently a few new purine nucleoside analogues (PNA) have been synthesized and introduced into preclinical and clinical trials. The transition-state theory has led to the design of 9-deazanucleotide analogues that are purine nucleoside phosphorylase (PNP) inhibitors, termed immucillins. Among them the most promising results have been obtained with forodesine. Forodesine (BCX-1777, Immucillin H, 1-(9-deazahypoxanthin)-1,4-dideoxy-1,4-imino-D-ribitol) has carbon-carbon linkage between a cyclic amine moiety that replaces ribose and 9-deaza-hypixanthine. The drug is a novel T-cell selective immunosuppressive agent which in the presence of 2'-deoxyguanosine (dGuo) inhibits human lymphocyte proliferation activated by various agents such as interleukin-2 (IL-2), mixed lymphocyte reaction and phytohemagglutinin. In the mechanism of forodesine action two enzymes are involved: PNP and deoxycytidine kinase (dCK). PNP catalyzes the phosphorolysis of dGuo to guanine (Gu) and 2'-deoxyribose-1-phosphate, whereas dCK converts dGuo to deoxyguanosino-5'-monophosphate (dGMP) and finally to deoxyguanosino-5'-triphosphate (dGTP). The affinity of dGuo is higher for PNP than for dCK. Nevertheless, if PNP is blocked by forodesine, plasma dGuo is not cleaved to Gu, but instead it is intracellularly converted to dGTP by high dCK activity, which leads to inhibition of ribonucleotide reductase (RR), an enzyme required for DNA synthesis and cell replication, which eventually results in apoptosis. Forodesine is active in some experimental tumors in mice, however it could be used for the treatment of human T-cell proliferative disorders and it is undergoing phase II clinical trials for the treatment of T-cell non-Hodgkin's lymphoma, which includes cutaneous T-cell lymphoma (CTCL). Moreover, recent preclinical and clinical data showed activity of forodesine in B-cell acute lympholastic leukemia (ALL).
Topics: Animals; Enzyme Inhibitors; Humans; Purine Nucleosides; Purine-Nucleoside Phosphorylase; Pyrimidinones
PubMed: 17897085
DOI: 10.2174/138955707781662636 -
The Journal of Organic Chemistry Jan 2020An efficient access to 6-substituted 7-deazapurine and the corresponding nucleosides by coupling aryl or alkyl Grignard reagents and halogenated purine nucleosides in...
An efficient access to 6-substituted 7-deazapurine and the corresponding nucleosides by coupling aryl or alkyl Grignard reagents and halogenated purine nucleosides in the presence of Fe(acac)/CuI is described. A series of 6-substituted 7-deazapurines and the corresponding nucleosides were obtained in medium to good yields. For the synthesis of modified nucleosides that will be the subject of biological testing, we propose to use iron-catalyzed instead of palladium-catalyzed reaction. The synthesized compounds were tested for their antiproliferative activity. The cytotoxicity study of compounds - shows that by modifying the 6-position of 7-deazapurine ribonucleosides, the compounds may become selective for certain cancer cell lines.
Topics: Catalysis; Cell Line, Tumor; Copper; Drug Screening Assays, Antitumor; Humans; Iron; Purine Nucleosides; Purines
PubMed: 31858795
DOI: 10.1021/acs.joc.9b02414 -
European Journal of Medicinal Chemistry Jan 2015Treating cancer has been challenging for decades, following countless approaches and attempts. Nucleosides, alone or as part of nucleotides, are vital elements of living...
Treating cancer has been challenging for decades, following countless approaches and attempts. Nucleosides, alone or as part of nucleotides, are vital elements of living systems and have shown pharmacological effects, e.g. as antibiotic or antiviral agents. We investigated the antitumor potential on human melanoma, lung and ovarian carcinomas, and on colon adenocarcinoma of a new series of purine nucleosides based on a 6-chloropurine or a 2-acetamido-6-chloropurine scaffold linked to perbenzylated hexosyl (glucosyl, galactosyl and mannosyl) residues. All compounds were tested in a sulforhodamine B (SRB) assay for their cytotoxicity and provided micromolar GI50 values with order of magnitude comparable to structurally similar chemotherapeutics, namely 2-chloro-2'-deoxyadenosine (cladribine). Furthermore, the induction of apoptosis was established and cell cycle analysis was accomplished demonstrating a G2/M cell cycle arrest.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; Cells, Cultured; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; G2 Phase Cell Cycle Checkpoints; HT29 Cells; Humans; Hydrocarbons, Halogenated; M Phase Cell Cycle Checkpoints; Mice; Molecular Structure; NIH 3T3 Cells; Purine Nucleosides; Structure-Activity Relationship
PubMed: 25499928
DOI: 10.1016/j.ejmech.2014.11.019 -
Proceedings of the National Academy of... Jan 2018Aqueous microdroplets (<1.3 µm in diameter on average) containing 15 mM d-ribose, 15 mM phosphoric acid, and 5 mM of a nucleobase (uracil, adenine, cytosine, or...
Aqueous microdroplets (<1.3 µm in diameter on average) containing 15 mM d-ribose, 15 mM phosphoric acid, and 5 mM of a nucleobase (uracil, adenine, cytosine, or hypoxanthine) are electrosprayed from a capillary at +5 kV into a mass spectrometer at room temperature and 1 atm pressure with 3 mM divalent magnesium ion (Mg) as a catalyst. Mass spectra show the formation of ribonucleosides that comprise a four-letter alphabet of RNA with a yield of 2.5% of uridine (U), 2.5% of adenosine (A), 0.7% of cytidine (C), and 1.7% of inosine (I) during the flight time of ∼50 µs. In the case of uridine, no catalyst is required. An aqueous solution containing guanine cannot be generated under the same conditions given the extreme insolubility of guanine in water. However, inosine can base pair with cytidine and thus substitute for guanosine. Thus, a full set of ribonucleosides to generate the purine-pyrimidine base pairs A-U and I-C are spontaneously generated in aqueous microdroplets under similar mild conditions.
Topics: Purine Nucleosides; Pyrimidine Nucleosides
PubMed: 29255025
DOI: 10.1073/pnas.1718559115 -
Journal of Medicinal Chemistry Jan 1996A series of 2'-deoxy-4'-thioribo purine nucleosides was prepared by trans-N-deoxyribosylase-catalyzed reaction of 2'-deoxy-4'-thiouridine with a variety of purine bases....
A series of 2'-deoxy-4'-thioribo purine nucleosides was prepared by trans-N-deoxyribosylase-catalyzed reaction of 2'-deoxy-4'-thiouridine with a variety of purine bases. This synthetic procedure is an improvement over methods previously used to prepare purine 4'-thio nucleosides. The compounds were tested against hepatitis B virus (HBV), human cytomegalovirus (HCMV), herpes simplex virus (HSV-1 and HSV-2), varicella zoster virus (VZV), and human immunodeficiency virus (HIV-1). Cytotoxicity was determined in a number of cell lines. Several compounds were extremely potent against HBV and HCMV and had moderate to severe cytotoxicity in vitro. The lead compound from the series, 2-amino-6-(cyclopropylamino)purine 2'-deoxy-4'-thioriboside, was the most potent and selective agent against HCMV and HBV replication in vitro; however, this analogue was nephrotoxic when tested in vivo.
Topics: Antiviral Agents; Cell Line; Cell Survival; HIV-1; Herpesviridae; Humans; Purine Nucleosides
PubMed: 8558524
DOI: 10.1021/jm950701k -
Clinica Chimica Acta; International... Feb 1979Rat lymphocytes incubated under hypoxic conditions in vitro show a time-dependent release of intracellular enzymes. As reported previously, enzyme release (lactate...
Rat lymphocytes incubated under hypoxic conditions in vitro show a time-dependent release of intracellular enzymes. As reported previously, enzyme release (lactate dehydrogenase) is decreased by metabolite, notably ATP and glucose, that contribute towards lymphocyte energy metabolism. The action of purine nucleosides in relation to enzyme release was investigated. Inosine was shown to decrease significantly lactate dehydrogenase release, whereas adenosine exerted a supportive action only at concentrations less than 0.5 mmol/l. Inosine decreased enzyme efflux maximally at concentrations of at least 2--3 mmol/l. The mechanism of inosine action was deduced to be primarily ribose 5-phosphate formation and its subsequent metabolism by energy-yielding pathways. Inosine was presumed also to enter the purine 'salvage pathway' and thereby maintain intracellular adenine nucleotide pools.
Topics: Adenosine; Adenosine Triphosphate; Animals; Glucose; In Vitro Techniques; Inosine; L-Lactate Dehydrogenase; Lymphocytes; Osmolar Concentration; Purine Nucleosides; Rats
PubMed: 421353
DOI: 10.1016/0009-8981(79)90401-7 -
European Journal of Biochemistry Sep 1982Dextran-bound adenosine, inosine, and nebularine have been prepared by carbodiimide coupling of their 2',3'-O-(4-carboxyethyl-1-methylbutylidene) cyclic acetal...
Dextran-bound adenosine, inosine, and nebularine have been prepared by carbodiimide coupling of their 2',3'-O-(4-carboxyethyl-1-methylbutylidene) cyclic acetal derivatives to 6-aminohexyldextran or 12-aminododecanyldextran. The latter polymers were prepared by cyanogen-bromide activation of dextran T80 followed by reaction with 1,6-diaminohexane or 1,12-diaminododecane. A high CNBr concentration leads to high-molecular-weight material, probably due to cross-linking, accompanied by a decrease in the digestion velocity using endo-dextranase from Penicillium species (EC 3.2.1.11). The dextran-bound nucleosides, as well as the nucleoside 2',3'-O-(4-ethoxycarbonyl-1-methylbutylidene) acetal derivatives, were tested as substrates and inhibitors for adenosine deaminase. The Km of the adenosine acetal ester is identical to that of adenosine which shows that acetalation does not hinder complex formation. Since the maximum velocity of deamination is decreased fourfold, the modified substrate does not fit as well as the nucleoside. The polymer-bound acetals show a 3-8-fold increase of Km or Ki and unchanged V compared to the corresponding acetals while dextranase digestion of the support does not alter the kinetic data. This indicates that the length of the polysaccharide chain does not interfere either with the complex formation or with the catalytic activity of the modified substrate. Since the activation energies of the deamination reactions of adenosine, its acetal ester, and dextran-linked adenosine are all similar (29.8-32.3 kJ mol-1) it is concluded that no diffusion control of the enzymatic reaction results from the binding of the nucleoside acetals to dextran T80.
Topics: Adenosine Deaminase; Adenosine Deaminase Inhibitors; Chemical Phenomena; Chemistry; Dextrans; Kinetics; Nucleoside Deaminases; Purine Nucleosides; Substrate Specificity; Thermodynamics
PubMed: 6183116
DOI: 10.1111/j.1432-1033.1982.tb06854.x -
Biochimica Et Biophysica Acta Jun 1977100 MHz proton magnetic resonance measurements were performed on dilute solutions of adenosine and guanosine and their 8MH2, 8-NHCH3 8-N(CH3)2 and 8-bromo derivatives....
100 MHz proton magnetic resonance measurements were performed on dilute solutions of adenosine and guanosine and their 8MH2, 8-NHCH3 8-N(CH3)2 and 8-bromo derivatives. The chemical shift of the ribose C2'-H and especially the difference in chemical shifts between the C1'-H and C2'-H resonances clearly indicated whether the nucleoside exists in a syn glycosyl conformation (the C8-dimethylamino derivatives) or as a flexible syn-anti mixture (the monomethylamino and amino derivatives). The temperature dependent behavior of these indicators can be employed to define qualitative shifs in syn-anti equilibrium with temperature. An increased C1'-H-C2'-H chemical shift separation implies shift to more anti, a decreased separation a shift to more syn conformers.
Topics: Adenosine; Guanosine; Magnetic Resonance Spectroscopy; Molecular Conformation; Purine Nucleosides; Ribose; Structure-Activity Relationship
PubMed: 884102
DOI: 10.1016/0005-2787(77)90290-8 -
Journal of the American Chemical Society Jul 1977
Topics: Adenine; Adenosine; Caffeine; Guanine; Guanosine; Hot Temperature; Hydrogen-Ion Concentration; Hypoxanthines; Inosine; Kinetics; Methods; Methylation; Photochemistry; Purine Nucleosides
PubMed: 17622
DOI: 10.1021/ja00457a033 -
Angewandte Chemie (International Ed. in... May 2006
Topics: Catalysis; Palladium; Purine Nucleosides; Solvents; Toluene
PubMed: 16639768
DOI: 10.1002/anie.200504565