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Chemistry & Biodiversity Sep 2010This review deals with 2-azapurine (imidazo[4,5-d] [1,2,3]triazine) nucleosides and closely related analogs. Different routes are described to yield the desired target... (Review)
Review
This review deals with 2-azapurine (imidazo[4,5-d] [1,2,3]triazine) nucleosides and closely related analogs. Different routes are described to yield the desired target compounds, including a sequence of ring-opening and ring-closure reactions performed on purine nucleosides or direct glycosylation of a 2-azapurine nucleobase with a sugar halide. Further, physical and spectroscopic properties of 2-azapurine nucleosides are discussed, including fluorescence, (13)C-NMR data, single-crystal X-ray analyses, and conformation studies on selected compounds; new biological data are presented. The second part of this review is dedicated to oligonucleotides containing 2-azapurines, including building-block (phosphoramidite) preparation and their use in solid-phase oligonucleotide synthesis. Base-pairing properties of 2-azapurine nucleosides as surrogates of canonical constituents of DNA were evaluated.
Topics: Antineoplastic Agents; Antiviral Agents; Aza Compounds; Base Pairing; Carbohydrate Conformation; Magnetic Resonance Spectroscopy; Oligonucleotides; Purine Nucleosides
PubMed: 20860023
DOI: 10.1002/cbdv.201000162 -
Nucleosides, Nucleotides & Nucleic Acids 2018Lactobacillus gasseri PA-3 (PA-3) is a bacterial strain with a strong ability to degrade purine nucleosides. We previously showed that PA-3 incorporates purines in vitro...
Lactobacillus gasseri PA-3 (PA-3) is a bacterial strain with a strong ability to degrade purine nucleosides. We previously showed that PA-3 incorporates purines in vitro and that oral administration of PA-3 and purines to rats attenuated their absorption of purines. It remains unclear whether these effects of PA-3 depend on bacterial strains. This study therefore compared the abilities of PA-3 and another bacterial strain of L. gasseri, OLL2996, which has shown decreased ability to degrade purine nucleosides in vitro, to incorporate purine nucleosides and to inhibit the absorption of purines fed to rats. Each bacterial strain was incubated in the presence of C-adenosine or C-inosine and the incorporation of each purine was evaluated by measuring their radioactivity. In vivo, rats were fed C-labeled purines along with PA-3 or OLL2996 and the absorption of these C-labeled purines was evaluated by analyzing radioactivity of blood samples. PA-3 incorporated about twice as much C-adenosine and C-inosine as OLL2996. The elevation of radioactivity levels in blood was 10-20% lower in rats treated with PA-3 than in control rats, after feeding with both C-adenosine and C-inosine as purines. In contrast, treatment with OLL2996 did not have statistically significant effects on radioactivity compared with the control group. These results indicate that the magnitude of bacterial inhibition of purine absorption is dependent on bacterial strain, correlating at least partly with the ability to incorporate and degrade purines.
Topics: Adenine; Adenosine; Animals; Carbon Radioisotopes; Gastric Absorption; Inosine; Lactobacillus gasseri; Male; Purine Nucleosides; Purines; Rats, Wistar; Species Specificity
PubMed: 29842848
DOI: 10.1080/15257770.2018.1469760 -
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 -
Science (New York, N.Y.) Oct 2019Theories about the origin of life require chemical pathways that allow formation of life's key building blocks under prebiotically plausible conditions. Complex...
Theories about the origin of life require chemical pathways that allow formation of life's key building blocks under prebiotically plausible conditions. Complex molecules like RNA must have originated from small molecules whose reactivity was guided by physico-chemical processes. RNA is constructed from purine and pyrimidine nucleosides, both of which are required for accurate information transfer, and thus Darwinian evolution. Separate pathways to purines and pyrimidines have been reported, but their concurrent syntheses remain a challenge. We report the synthesis of the pyrimidine nucleosides from small molecules and ribose, driven solely by wet-dry cycles. In the presence of phosphate-containing minerals, 5'-mono- and diphosphates also form selectively in one-pot reactions. The pathway is compatible with purine synthesis, allowing the concurrent formation of all Watson-Crick bases.
Topics: Chemical Phenomena; Hydroxylamine; Purine Nucleosides; Purine Nucleotides; Pyrimidine Nucleosides; Pyrimidine Nucleotides; RNA; Ribonucleotides; Ribose
PubMed: 31604305
DOI: 10.1126/science.aax2747 -
Current Pharmaceutical Design 2012Purine nucleoside analogues (PNA) are the cytotoxic agents highly active in the treatment of indolent lymphoid malignancies. These drugs have chemical structure similar... (Review)
Review
Purine nucleoside analogues (PNA) are the cytotoxic agents highly active in the treatment of indolent lymphoid malignancies. These drugs have chemical structure similar to adenosine or deoxyadenosine. PNAs are characterized by a similar mechanism of cytotoxicity both in proliferating and quiescent cells, such as inhibition of DNA synthesis, inhibition of DNA repair and accumulation of DNA strand breaks. In addition, PNAs induce apoptosis which is the end-point of their action. Older PNAs, pentostatin (DCF; 2'- deoxycoformycin), cladribine (2-CdA; 2-chloro-2'-deoxyadenosine) and fludarabine (2-fluoro-9-(-D-arabinosyl)-adenine) were approved by Food and Drug Administration (FDA) for the treatment of hematological malignancies. In addition three novel PNAs: clofarabine (CAFdA), nelarabine (ara-G) and forodesine (immucillin H, BCX-1777) have been synthesized and introduced into preclinical studies and clinical trials. This review summarizes current knowledge on the mechanism of action and pharmacokinetic properties of older and new PNAs. Clinical activity and toxicity of PNAs, especially in hairy cell leukemia (HCL), hairy cell leukemia variant (HCL-V), prolymphocytic leukemia (PLL) and other rarer chronic lymphoid leukemias, are also presented. 2-CdA and DCF, introduced in the 1980s, changed radically the treatment modality, inducing complete and durable responses in the majority of patients with HCL. In contrast, the results of the treatment of HCL-V with PNA are rather poor. There are also several reports indicating activity of PNAs in PLL and large granular lymphocyte leukemia. Clofarabine, nelarabine and forodesine need further investigation in rarer lymphid leukemias, to better define their status in the treatment of these disorders.
Topics: Antineoplastic Agents; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Purine Nucleosides
PubMed: 22591387
DOI: 10.2174/138161212801227005 -
Current Topics in Medicinal Chemistry Oct 2002Ring-expanded (ldauo;fat") nucleosides (RENs) described in this review are analogues of purine nucleosides containing a 5:7-fused imidazodiazepine or imidazotriazepine... (Review)
Review
Ring-expanded (ldauo;fat") nucleosides (RENs) described in this review are analogues of purine nucleosides containing a 5:7-fused imidazodiazepine or imidazotriazepine ring system. They are both of natural and synthetic origin, and are of chemical, biochemical, biophysical, as well as medicinal interest. The important natural RENs include coformycin, pentostatin, azepinomycin, adechlorin, and adecypenol. A majority of them are synergistic antitumor and/or antiviral antibiotics which potentiate the effects of other antitumor or antiviral compounds through inhibition of key enzymes such as adenosine deaminase or guanase which would otherwise metabolically degrade the active compounds into therapeutically less potent or totally inactive counterparts. However, despite the fact that some of the natural RENs such as coformycins are the strongest known enzyme inhibitors, they have not been proven as effective clinically as anticipated because of the extremely high toxicity associated with their use. Nevertheless, pentostatin (2'-deoxycoformycin) is a conspicuous exception as it is gaining wide attention in recent years as a clinically effective therapeutic agent against leukemias and lymphomas. Many of the recently reported synthetic RENs, by contrast, possess biological activities of their own, in particular against a wide spectrum of cancers and viruses with little toxicity to the host cells, and thus hold considerable promise as chemotherapeutic agents. The promising preliminary in vitro data concerning the effects of RENs on human cancers, in particular prostate and breast cancer cells, support their further pursuit in animal and clinical studies. RENs also carry promise against many viral infections belonging to the families of hepatitis, herpes, and respiratory infections, most notable being the hepatitis B (HBV), hepatitis C (HCV), and the West Nile (WNV) viruses.
Topics: Antineoplastic Agents; Antiviral Agents; Azepines; Enzyme Inhibitors; Humans; Purine Nucleosides; Structure-Activity Relationship; Triazenes
PubMed: 12173969
DOI: 10.2174/1568026023393147 -
Recent Patents on Anti-cancer Drug... Jun 2008Recently, the search for more effective and safer antineoplastic agents has led to synthesis and introduction into preclinical and clinical studies of a few new purine... (Review)
Review
Recently, the search for more effective and safer antineoplastic agents has led to synthesis and introduction into preclinical and clinical studies of a few new purine nucleoside analogues (PNA). Three of them: clofarabine (CAFdA), nelarabine, and forodesine (immucillin H, BCX-1777), despite belonging to the same group of drugs such as PNA, have shown some differences concerning their active forms, metabolic properties and mechanism of action. However, all these drugs have demonstrated promising activity in patients with relapsed and refractory acute lymphoblastic leukemia (ALL). CAFdA was approved for the therapy of relapsed or refractory ALL in the third line of treatment. It has proved promising in pediatric patients as well as in some patients who are able to proceed to allogenic hematopietic stem cell transplantation (HSCT). Moreover, the drug exhibits an efficacy in acute myeloid leukemia (AML), blast crisis of chronic myelogenous leukemia (CML-BP) and myelodysplastic syndrome (MDS). Nelarabine is recommended for T-ALL and T-cell lymphoblastic lymphoma (T-LBL) with the overall response rates ranging from 11 to 60%. However, the use of the drug is limited by potentially severe neurotoxicity. Forodesine is a purine nucleoside phosphorylase (PNP) inhibitor and it has shown activity in relapsed and refractory T- and B-cells leukemias as well as in cutaneous T-cell lymphoma (CTCL). Recently patented, a few of inventions in the field of pharmaceutical preparation of new PNA have also been published. Great hopes are currently set on the use of these drugs in the treatment of lymphoid and myeloid malignancies in adult and in pediatric patients, however ongoing studies will help to define their role in the standard therapy.
Topics: Adenine Nucleotides; Antineoplastic Agents; Arabinonucleosides; Clinical Trials as Topic; Clofarabine; Hematologic Neoplasms; Humans; Purine Nucleosides; Pyrimidinones
PubMed: 18537755
DOI: 10.2174/157489208784638811 -
Farmaco (Societa Chimica Italiana :... Mar 2003A number of ligands for the adenosine binding sites has been obtained by using nucleoside convergent and divergent synthesis. Most of our nucleosides have been...
A number of ligands for the adenosine binding sites has been obtained by using nucleoside convergent and divergent synthesis. Most of our nucleosides have been synthesized by coupling 2,6-dichloropurine (1), 2,6-dichloro-1-deazapurine (2), 2,6-dichloro-3-deazapurine (3) with ribose, 2- and 3-deoxyribose and 2,3-dideoxyribose derivatives. The use of these versatile synthons allowed the introduction of various substituents in 2- and/or 6-positions. The glycosylation site and the anomeric configuration of the obtained nucleosides were assigned on the basis of spectroscopic studies and confirmed by molecular models. A series of potent adenosine receptor ligands has been obtained by using divergent approaches, mostly starting from guanosine. Substitutions in 2, 6, 8, and 5' position of adenosine molecule led to ligands selective for the different adenosine receptor subtypes. Furthermore, we investigated the molecular bases of the different behavior of 2- and 8-alkynyl adenosines, by means of NMR experiments and molecular modeling studies. With docking experiments, we demonstrated that the two class of molecules should have different binding modes that explain their different degree of affinity and the shift of their activity from agonistic (2-substituted derivatives) to antagonistic (8-substituted derivatives).
Topics: Animals; Binding Sites; CHO Cells; Cricetinae; Humans; Models, Molecular; Purine Nucleosides; Tubercidin
PubMed: 12620415
DOI: 10.1016/S0014-827X(03)00019-3 -
Science (New York, N.Y.) May 2016The origin of life is believed to have started with prebiotic molecules reacting along unidentified pathways to produce key molecules such as nucleosides. To date, a...
The origin of life is believed to have started with prebiotic molecules reacting along unidentified pathways to produce key molecules such as nucleosides. To date, a single prebiotic pathway to purine nucleosides had been proposed. It is considered to be inefficient due to missing regioselectivity and low yields. We report that the condensation of formamidopyrimidines (FaPys) with sugars provides the natural N-9 nucleosides with extreme regioselectivity and in good yields (60%). The FaPys are available from formic acid and aminopyrimidines, which are in turn available from prebiotic molecules that were also detected during the Rosetta comet mission. This nucleoside formation pathway can be fused to sugar-forming reactions to produce pentosides, providing a plausible scenario of how purine nucleosides may have formed under prebiotic conditions.
Topics: Formates; Meteoroids; Origin of Life; Prebiotics; Purine Nucleosides; Pyrimidines; RNA
PubMed: 27174989
DOI: 10.1126/science.aad2808 -
Journal of Chromatography. A Aug 2014Improved nitrogen utilization in cattle is important in order to secure a sustainable cattle production. As purines and pyrimidines (PP) constitute an appreciable part...
Simultaneous quantification of purine and pyrimidine bases, nucleosides and their degradation products in bovine blood plasma by high performance liquid chromatography tandem mass spectrometry.
Improved nitrogen utilization in cattle is important in order to secure a sustainable cattle production. As purines and pyrimidines (PP) constitute an appreciable part of rumen nitrogen, an improved understanding of the absorption and intermediary metabolism of PP is essential. The present work describes the development and validation of a sensitive and specific method for simultaneous determination of 20 purines (adenine, guanine, guanosine, inosine, 2'-deoxyguanosine, 2'-deoxyinosine, xanthine, hypoxanthine), pyrimidines (cytosine, thymine, uracil, cytidine, uridine, thymidine, 2'-deoxyuridine), and their degradation products (uric acid, allantoin, β-alanine, β-ureidopropionic acid, β-aminoisobutyric acid) in blood plasma of dairy cows. The high performance liquid chromatography-based technique coupled to electrospray ionization tandem mass spectrometry (LC-MS/MS) was combined with individual matrix-matched calibration standards and stable isotopically labelled reference compounds. The quantitative analysis was preceded by a novel pre-treatment procedure consisting of ethanol precipitation, filtration, evaporation and reconstitution. Parameters for separation and detection during the LC-MS/MS analysis were investigated. It was confirmed that using a log-calibration model rather than a linear calibration model resulted in lower CV% and a lack of fit test demonstrated a satisfying linear regression. The method covers concentration ranges for each metabolite according to that in actual samples, e.g. guanine: 0.10-5.0 μmol/L, and allantoin: 120-500 μmol/L. The CV% for the chosen quantification ranges were below 25%. The method has good repeatability (CV%≤25%) and intermediate precision (CV%≤25%) and excellent recoveries (91-107%). All metabolites demonstrated good long-term stability and good stability within-runs (CV%≤10%). Different degrees of absolute matrix effects were observed in plasma, urine and milk. The determination of relative matrix effects revealed that the method was suitable for almost all examined PP metabolites in plasma drawn from an artery and the portal hepatic, hepatic and gastrosplenic veins and, with a few exceptions, also for other species such as chicken, pig, mink, human and rat.
Topics: Animals; Calibration; Cattle; Chromatography, High Pressure Liquid; Humans; Milk; Mink; Purine Nucleosides; Pyrimidine Nucleosides; Rats; Reference Standards; Spectrometry, Mass, Electrospray Ionization; Swine; Tandem Mass Spectrometry
PubMed: 25017393
DOI: 10.1016/j.chroma.2014.06.065