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Nucleosides, Nucleotides & Nucleic Acids 2021Antimetabolites, which are metabolic antagonists used in the treatment of cancer and viral diseases by replacing metabolites, inhibit the action of metabolic enzymes and...
Antimetabolites, which are metabolic antagonists used in the treatment of cancer and viral diseases by replacing metabolites, inhibit the action of metabolic enzymes and disrupt the pathways of synthesis of structural units necessary for the formation of nucleic acids. Purine antagonists, that are subunits of antimetabolites, reduce the production of purine bases, and hence, cause the nucleotide production to stop and bring about the death of cancer cells. Fludarabine (2-fluoro-ara-AMP), which is used in chemotherapy, is an antimetabolite of the purine class containing mono phosphate in its structure. In this study, a protocol was presented to effectively and efficiently synthesis of 6-(4-phenylpiperazine-1-yl)-9-(β-D-ribofuranosyl)-9-purine-5'- O-phosphate compound in six steps and 25% overall yield starting with commercially available 6-chloropurine.
Topics: Models, Molecular; Molecular Conformation; Phosphorylation; Purine Nucleosides; Stereoisomerism
PubMed: 33416028
DOI: 10.1080/15257770.2020.1843679 -
Current Protocols in Nucleic Acid... Dec 2020The protocols presented in this article describe highly detailed synthesis of trifluoromethylated purine nucleotides and nucleosides (G and A). The procedure involves...
The protocols presented in this article describe highly detailed synthesis of trifluoromethylated purine nucleotides and nucleosides (G and A). The procedure involves trifluoromethylation of properly protected (acetylated) nucleosides, followed by deprotection leading to key CF -containing nucleosides. This gives synthetic access to 8-CF -substituted guanosine derivatives and three adenosine derivatives (8-CF , 2-CF , and 2,8-diCF ). In further steps, phosphorylation and phosphate elongation (for selected examples) result in respective trifluoromethylated nucleoside mono-, di-, and triphosphates. Support protocols are included for compound handling, purification procedures, analytical sample preparation, and analytical techniques used throughout the performance of the basic protocols. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Synthesis of trifluoromethylated guanosine and adenosine derivatives Basic Protocol 2: Synthesis of trifluoromethylated guanosine and adenosine monophosphates Basic Protocol 3: Synthesis of phosphorimidazolides of GMP and AMP Basic Protocol 4: Synthesis of trifluoromethylated guanosine and adenosine oligophosphates Support Protocol 1: TLC sample preparation and analysis Support Protocol 2: Purification protocol for Basic Protocol 1 Support Protocol 3: HPLC analysis and preparative HPLC Support Protocol 4: Ion-exchange chromatography.
Topics: Fluorine; Methylation; Purine Nucleosides; Purines; Ribonucleotides; Spectrum Analysis
PubMed: 32991077
DOI: 10.1002/cpnc.118 -
Molecules (Basel, Switzerland) Mar 2021The de novo synthesis of piperidine nucleosides from our homologating agent 5,6-dihydro-1,4-dithiin is herein reported. The structure and conformation of nucleosides...
The de novo synthesis of piperidine nucleosides from our homologating agent 5,6-dihydro-1,4-dithiin is herein reported. The structure and conformation of nucleosides were conceived to faithfully resemble the well-known nucleoside drugs Immucillins H and A in their bioactive conformation. NMR analysis of the synthesized compounds confirmed that they adopt an iminosugar conformation bearing the nucleobases and the hydroxyl groups in the appropriate orientation.
Topics: Adenine; Adenosine; Magnetic Resonance Spectroscopy; Molecular Conformation; Nucleosides; Piperidines; Purine Nucleosides; Pyrimidinones; Pyrrolidines; Structure-Activity Relationship
PubMed: 33809603
DOI: 10.3390/molecules26061652 -
Nucleosides, Nucleotides & Nucleic Acids 2004Some 4'-C-ethynyl-2'-deoxy purine nucleosides showed the most potent anti-HIV activity among the series of 4'-C-substituted 2'-deoxynucleosides whose 4'-C-substituents...
Some 4'-C-ethynyl-2'-deoxy purine nucleosides showed the most potent anti-HIV activity among the series of 4'-C-substituted 2'-deoxynucleosides whose 4'-C-substituents were methyl, ethyl, ethynyl and so on. Our hypothesis is that the smaller the substituent at the C-4' position they have, the more acceptable biological activity they show. Thus, 4'-C-cyano-2'-deoxy purine nucleosides, whose substituent is smaller than the ethynyl group, will have more potent antiviral activity. To prove our hypothesis, we planned to develop an efficient synthesis of 4'-C-cyano-2'-deoxy purine nucleosides (4'-CNdNs) and 4'-C-ethynyl-2'-deoxy purine nucleosides (4'-EdNs). Consequently, we succeeded in developing an efficient synthesis of six 2'-deoxy purine nucleosides bearing either a cyano or an ethynyl group at the C-4' position of the sugar moiety from 2'-deoxyadenosine and 2,6-diaminopurine 2'-deoxyriboside. Unfortunately, 4'-C-cyano derivatives showed lower activity against HIV-1, and two 4'-C-ethynyl derivatives suggested high toxicity in vivo.
Topics: Animals; Anti-HIV Agents; Cell Line; Drug Design; Female; HIV Infections; HIV-1; Humans; Mice; Purine Nucleosides; Virus Replication
PubMed: 15200030
DOI: 10.1081/NCN-120037508 -
Pharmacology & Therapeutics 1991Recent investigations have identified many new purine nucleoside analogs that act as antimetabolites. This article focuses on the metabolism and mechanisms of action of... (Review)
Review
Recent investigations have identified many new purine nucleoside analogs that act as antimetabolites. This article focuses on the metabolism and mechanisms of action of tiazofurin, 3-deazaguanosine, neplanocin A, arabinosyladenine in combination with inhibitors of adenosine deaminase, arabinosyl-2-fluoroadenine, and 2-chloro-2'-deoxyadenosine, drugs that are either currently being evaluated in clinical trials or are close to that stage. The diverse metabolic requirements for activation, unique mechanisms of action, and differential biological activities of these compounds are characterized and evaluated for prospective therapeutic application.
Topics: 2-Chloroadenosine; Adenosine; Cladribine; Deoxyadenosines; Guanine; Guanosine; Humans; Purine Nucleosides; Ribavirin; Vidarabine
PubMed: 1675805
DOI: 10.1016/0163-7258(91)90057-s -
FEMS Microbiology Letters Sep 2003The effect of purine nucleosides on the in vitro growth of Cryptosporidium parvum was studied. Culturing the parasite in THP-1 cells for 72 h in growth medium...
The effect of purine nucleosides on the in vitro growth of Cryptosporidium parvum was studied. Culturing the parasite in THP-1 cells for 72 h in growth medium supplemented with adenosine or inosine improved the parasite yields especially in the first 48 h. Similar results were obtained with parasites cultured in Madin-Darby bovine kidney cells and incubated for 24 h with inosine. The addition of inosine to 72-h cultures enhanced the growth of C. parvum in THP-1 cells, especially the trophic stages, whereas the analogue formycin B was toxic to the parasites and induced a marked decrease in the gamont stages. The monitoring of the added purine nucleosides by high performance liquid chromatography showed that at 37 degrees C in the presence of THP-1 cells, a rapid uptake of inosine occurred with hypoxanthine being the main purine present after 2 h in the medium.
Topics: Adenosine; Animals; Cattle; Cell Line; Chromatography, High Pressure Liquid; Cryptosporidium parvum; Culture Media; Formycins; Humans; Hypoxanthine; Inosine; Purine Nucleosides
PubMed: 13129605
DOI: 10.1016/S0378-1097(03)00555-X -
Clinical Biochemistry Jun 2021Recently, the enzyme nudix hydrolase 15 (NUDT15) has been identified as an additional component of the thiopurine metabolism pathway. NUDT15 (also known as MTH2)... (Review)
Review
Recently, the enzyme nudix hydrolase 15 (NUDT15) has been identified as an additional component of the thiopurine metabolism pathway. NUDT15 (also known as MTH2) catalyzes the dephosphorylation of 6-thioguanosine triphosphate (6-TGTP) and 6-thio-deoxyguanosine triphosphate (6-TdGTP), which is the active metabolite of thiopurine medications. Thiopurine compounds, which were first synthesized in the 1950s, are widely used in the treatment of childhood leukemia, inflammatory bowel disease, and autoimmune disorders. For many years, TPMT has been recognized as an enzyme that is involved in thiopurine metabolism, and interindividual variation in TPMT activity has been known to contribute to differences in risk of thiopurine toxicity. Genetic variation that leads to decreased NUDT15 activity has been recognized as an additional contributor, beyond TPMT, to thiopurine toxicity. In some populations, including Asian and Latino populations, NUDT15 genetic variants are more common than TPMT variants, making this a significant biomarker of toxicity. Clinical genetic testing is now available for a subset of NUDT15 variants, representing a remarkably fast translation from bench to bedside. This review will focus on NUDT15 - from discovery to clinical implementation.
Topics: Asian People; Hispanic or Latino; Humans; Inflammatory Bowel Diseases; Methyltransferases; Mutation; Pharmacogenomic Variants; Purine Nucleosides; Pyrophosphatases; Thionucleosides
PubMed: 33675810
DOI: 10.1016/j.clinbiochem.2021.02.007 -
Archives of Pharmacal Research May 2017Nucleoside analogues play an important role in antiviral, antibacterial and antineoplastic chemotherapy. Herein we report the synthesis, structural characterization and...
Nucleoside analogues play an important role in antiviral, antibacterial and antineoplastic chemotherapy. Herein we report the synthesis, structural characterization and biological activity of some 4'-C -methyl- and -phenyl dioxolane-based nucleosides. In particular, α and β anomers of all natural nucleosides were obtained and characterized by NMR, HR-MS and X-ray crystallography. The compounds were tested for antimicrobial activity against some representative human pathogenic fungi, bacteria and viruses. Antitumor activity was evaluated in a large variety of human cancer cell-lines. Although most of the compounds showed non-significant activity, 23α weakly inhibited HIV-1 multiplication. Moreover, 22α and 32α demonstrated a residual antineoplastic activity, interestingly linked to the unnatural α configuration. These results may provide structural insights for the design of active antiviral and antitumor agents.
Topics: Anti-HIV Agents; Antineoplastic Agents; Cell Line; Cell Proliferation; Crystallography, X-Ray; Dioxolanes; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HIV-1; Humans; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Purine Nucleosides; Pyrimidine Nucleosides; Structure-Activity Relationship
PubMed: 27615010
DOI: 10.1007/s12272-016-0825-6 -
Organic Letters Nov 2022A method for the C-H carboxyamidation of purines has been developed that is capable of directly installing primary, secondary, and tertiary amides. Previous Minisci-type...
A method for the C-H carboxyamidation of purines has been developed that is capable of directly installing primary, secondary, and tertiary amides. Previous Minisci-type investigations on purines were limited to alkylations and arylations. Herein, we present the first method for the direct C-H amidation of a wide range of purines: xanthine, guanine, and adenine structures, including guanosine- and adenosine-type nucleosides. The Minisci-type reaction is also metal-free, cheap, operationally simple, scalable, and applicable to late-stage functionalizations of biologically important molecules.
Topics: Purines; Adenine; Guanine; Guanosine; Nucleosides; Purine Nucleosides
PubMed: 36285836
DOI: 10.1021/acs.orglett.2c03206 -
Nucleic Acids Research Apr 1974The structural effects of chemical modifications upon the affinity of purine nucleosides to cytidine-transport system in Bacillus subtilis were investigated using a...
The structural effects of chemical modifications upon the affinity of purine nucleosides to cytidine-transport system in Bacillus subtilis were investigated using a series of modified derivatives. The interaction involves protein molecule(s) which require the presence and proper orientation of the sugar residue and its hydroxylic functions. Moreover, a specific interaction with the heterocyclic ring system is involved in the process which results in a requirement for an aromatic pi -electron system and an absence of a polarizable function at position 6 of the purine heterocycle. The region in the protein responsible for the latter interaction is rather limited and, consequently, a proper nucleoside conformation is required.
Topics: Bacillus subtilis; Biological Transport, Active; Cytidine; Kinetics; Nucleosides; Purine Nucleosides
PubMed: 10793745
DOI: 10.1093/nar/1.4.639