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European Journal of Medicinal Chemistry Sep 2018A focused nucleoside library was constructed around a 3'-C-ethynyl-d-ribofuranose sugar scaffold, which was coupled to variously modified purine nucleobases. The...
A focused nucleoside library was constructed around a 3'-C-ethynyl-d-ribofuranose sugar scaffold, which was coupled to variously modified purine nucleobases. The resulting nucleosides were probed for their ability to inhibit tumor cell proliferation, as well as for their activity against a panel of relevant human viruses. While C6-aryl substituted purine nucleosides were found to be weakly active, several C7-substituted 7-deazapurine nucleosides elicited potent antiproliferative activity. Their activity spectrum was evaluated in the NCI-60 tumor cell line panel indicating activity against several solid tumor derived cell lines. Analog 32, equipped with a 7-deaza 7-chloro-6-amino-purin-9-yl base was evaluated in a metastatic breast tumor (MDA-MB-231-LM2) xenograft model. It inhibited both tumor growth and reduced the formation of lung metastases as revealed by BLI analysis. The dideazanucleoside analog 66 showed interesting activity against hCMV. These results highlight the potential advantages of recombining known sugar and nucleobase motifs as a library design strategy to discover novel antiviral or antitumor agents.
Topics: Antineoplastic Agents; Antiviral Agents; Cell Line, Tumor; Cell Proliferation; Cytomegalovirus; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Humans; Microbial Sensitivity Tests; Molecular Structure; Nucleosides; Purine Nucleosides; Small Molecule Libraries; Structure-Activity Relationship; Vaccinia virus
PubMed: 30098481
DOI: 10.1016/j.ejmech.2018.07.062 -
European Journal of Cell Biology Mar 2004Mammalian neurons require a constant supply of oxygen to maintain adequate cellular functions and survival. Following sustained hypoxia during ischemic events in brain,... (Comparative Study)
Comparative Study
Mammalian neurons require a constant supply of oxygen to maintain adequate cellular functions and survival. Following sustained hypoxia during ischemic events in brain, the energy status of neurons and glia is compromised, which may subsequently lead to cell death by apoptosis and necrosis. Concomitant with energy depletion is the formation of the purine nucleoside adenosine, a powerful endogenous neuroprotectant. In this paper the effect of chemical hypoxia on cell survival and neurite outgrowth of primary cerebellar granule cells was investigated. Rotenone, a mitochondrial complex I inhibitor, induced a 30.4 +/- 3.6% loss of viable cells and a 35.0 +/- 4.4% loss of neurite formation of cerebellar granule cells, which was partially restored by the addition of purine nucleosides adenosine, inosine and guanosine. Inosine had the most striking effect of 37.7 +/- 2.9% rescue of viability and 71.2 +/- 18.4% rescue of neurite outgrowth. Data confirm the suggested role of purine nucleosides for the neuronal regeneration of primary brain cells following hypoxic insult.
Topics: Adenosine; Animals; Cell Hypoxia; Cell Survival; Cells, Cultured; Cerebellum; Guanosine; Inosine; Neurites; Neuroprotective Agents; Purine Nucleosides; Rats; Rats, Sprague-Dawley; Rotenone; Time Factors; Uncoupling Agents
PubMed: 15146976
DOI: 10.1078/0171-9335-00362 -
Synthesis of novel purine nucleosides towards a selective inhibition of human butyrylcholinesterase.Bioorganic & Medicinal Chemistry Jul 2009The search for new and potent cholinesterase inhibitors is an ongoing quest mobilizing many organic chemistry groups around the world as these molecules have been shown...
The search for new and potent cholinesterase inhibitors is an ongoing quest mobilizing many organic chemistry groups around the world as these molecules have been shown to treat the late symptoms of Alzheimer's disease as well as to act as neuroprotecting agents. In this work, we disclose the synthesis of novel 2-acetamidopurine nucleosides and, for the first time, regioselective N(7)-glycosylation with 2-acetamido-6-chloropurine, promoted by trimethylsilyl triflate, was accomplished by tuning the reaction conditions (acetonitrile as solvent, 65 degrees C, 5h) starting from 1-acetoxy bicyclic glycosyl donors, or by direct coupling of a methyl glucopyranoside with the nucleobase to obtain only N(7) nucleosides in reasonable yield (55-60%). The nucleosides as well as their sugar precursors were screened for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. While none of the compounds tested inhibited AChE, remarkably, some of the N(7) nucleosides and sugar bicyclic derivatives showed potent inhibition towards BChE. Nanomolar inhibition was obtained for one compound competing well with rivastigmine, a drug currently in use for the treatment of Alzheimer's disease. Experimental results showed that the presence of benzyl groups on the carbohydrate scaffold and the N(7)-linked purine nucleobase were necessary for strong BChE inactivation. A preliminary evaluation of the acute cytotoxicity of the elongated bicyclic sugar precursors and nucleosides was performed indicating low values, in the same order of magnitude as those of rivastigmine.
Topics: Alzheimer Disease; Butyrylcholinesterase; Cell Line; Cell Survival; Cholinesterase Inhibitors; Fibroblasts; Glycosylation; Humans; Purine Nucleosides; Stereoisomerism
PubMed: 19520578
DOI: 10.1016/j.bmc.2009.05.057 -
Organic & Biomolecular Chemistry Oct 2011Natural nucleotides are not useful as fluorescent probes because of their low quantum yields. Therefore, a common methodology for the detection of RNA and DNA is the...
Natural nucleotides are not useful as fluorescent probes because of their low quantum yields. Therefore, a common methodology for the detection of RNA and DNA is the application of extrinsic fluorescent dyes coupled to bases in oligonucleotides. To overcome the many limitations from which fluorescent nucleotide-dye conjugates suffer, we have developed novel purine nucleosides with intrinsic fluorescence to be incorporated into oligonucleotide probes. For this purpose we synthesized adenosine and guanosine fluorescent analogues 7-25, conjugated at the C8 position with aryl/heteroaryl moieties either directly, or via alkenyl/alkynyl linkers. Directly conjugated analogues 7-14, exhibited high quantum yields, φ >0.1, and short λ(em) (<385 nm). Alkynyl conjugated analogues 22-25, exhibited low quantum yields, φ <0.075, and λ(em)<385 nm. The alkenyl conjugated analogues 15-21, exhibited λ(em) 408-459 nm. While analogues 15,16, and 20 bearing an EDG on the aryl moiety, exhibited φ <0.02, analogues 17, and 21 with EWG on the aryl moiety, exhibited extremely high quantum yields, φ ≈ 0.8, suggesting better intramolecular charge transfer. We determined the conformation of selected adenosine analogues. Directly conjugated analogue 8 and alkynyl conjugated analogue 22, adapted the syn conformation, whereas alkenyl conjugated analogue 15 adapted the anti conformation. Based on the long emission wavelengths, high quantum yields, anti conformation and base-paring compatibility, we suggest analogues 17 and 21 for further development as fluorescent probes for the sensitive detection of genetic material.
Topics: Base Pairing; DNA; Fluorescence; Fluorescent Dyes; Magnetic Resonance Spectroscopy; Nucleic Acid Conformation; Oligonucleotides; Phenols; Purine Nucleosides; Quantum Theory; RNA; Spectrometry, Fluorescence; Staining and Labeling
PubMed: 21960279
DOI: 10.1039/c1ob05681f -
Organic & Biomolecular Chemistry May 2016An efficient route to synthesize cycloalkyl substituted purine nucleosides was developed. This metal-free C-H activation was accomplished by a tBuOOtBu initiated radical...
An efficient route to synthesize cycloalkyl substituted purine nucleosides was developed. This metal-free C-H activation was accomplished by a tBuOOtBu initiated radical reaction. By adjusting the amount of tBuOOtBu and reaction time, the selective synthesis of C6-monocycloalkyl or C6,C8-dicycloalkyl substituted purine nucleosides could be realized. Furthermore, uracil and related nucleosides were also suitable substrates, giving the C5-cyclohexyl substituted uracil derivatives in good yields with excellent regioselectivities.
Topics: Alkanes; Chemistry Techniques, Synthetic; Free Radicals; Purine Nucleosides
PubMed: 27101306
DOI: 10.1039/c6ob00596a -
Critical Reviews in Eukaryotic Gene... 2011C8-Aryl purines, their nucleosides, and phosphoramidites has been synthetic targets for more than 60 years. Interest in these compounds stems from their utility as... (Review)
Review
C8-Aryl purines, their nucleosides, and phosphoramidites has been synthetic targets for more than 60 years. Interest in these compounds stems from their utility as fluorescent markers, they have therapeutic uses, are biomarkers, biomolecular probes, supramolecular building blocks, and for conformational studies. Until recently, the selective arylation of the C8-position of purines has been a challenging task. Several approaches have been explored including building them up from a pyrimidine or selective C8-modification of an unsubstituted purine. Neither of these approaches has proven to have broad scope. The discovery that C8-aryl purine nucleosides can be made via the Suzuki cross-coupling reaction has allowed a diverse array of analogues to be prepared and, in turn, the corresponding phosphoramidites. The latter is particularly significant as C8-aryl purine adducts are a major mutation observed from aromatic carcinogens and ready access to C8-aryl phosphoramidites will facilitate the synthesis and study of C8-aryl purine biomarkers and modified oligonucleotides.
Topics: Biomarkers; DNA Damage; Molecular Conformation; Oligonucleotides; Organophosphorus Compounds; Purine Nucleosides; Purines; Pyrimidines
PubMed: 22077154
DOI: 10.1615/critreveukargeneexpr.v21.i2.50 -
Cancer Treatment Reviews Dec 2013Purine nucleoside analogs (PNAs) compose a class of cytotoxic drugs that have played an important role in the treatment of hematological neoplasms, especially lymphoid... (Review)
Review
Purine nucleoside analogs (PNAs) compose a class of cytotoxic drugs that have played an important role in the treatment of hematological neoplasms, especially lymphoid and myeloid malignancies. All PNA drugs have a chemical structure similar to adenosine or guanosine, and they have similar mechanisms of action. They have many intracellular targets: they act as antimetabolites, competing with natural nucleosides during DNA or RNA synthesis, and as inhibitors of key cell enzymes. In contrast to other antineoplastic drugs, PNAs act cytotoxically, both in the mitotic and quiescent cell cycle phases. In the last few years, three PNAs have been approved for the treatment of lymphoid malignancies and other hematological disorders: 2-chlorodeoxyadenosine (2-CdA), fludarabine and pentostatin. 2-CdA and fludarabine are also active in the treatment of acute myeloid leukemia (AML). These drugs, in combination with cytarabine and other agents, are commonly used as salvage regimens in relapsed or refractory AML. Moreover, the addition of 2-CdA to the standard induction regimen is associated with an increased rate of complete remission and improved survival of adult patients with AML. More recently three novel PNAs have been synthesized and introduced into clinical trials: clofarabine, nelarabine and forodesine. Clofarabine is the most promising PNA in current clinical trials in pediatric and adult patients with acute leukemias. Nelarabine is more cytotoxic in T-lineage than in B-lineage leukemias. Clofarabine and nelarabine have been approved for the treatment of refractory patients with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma. Clofarabine is also an active drug in AML treatment when administered either alone or in combination regimens as front-line treatment and in relapsed or refractory patients. Unlike other PNA, forodesine is not incorporated into DNA but displays a highly selective purine nucleoside phosphorylase inhibitory action. Forodesine is undergoing clinical trials for the treatment of T-cell malignancies, including T-cell ALL. This article summarizes recent achievements in the mechanism of action, pharmacological properties and clinical activity and toxicity of PNAs, as well as their emerging role in lymphoid and myeloid acute leukemias.
Topics: Acute Disease; Cell Growth Processes; Humans; Leukemia; Purine Nucleosides
PubMed: 23566572
DOI: 10.1016/j.ctrv.2013.03.006 -
Nucleic Acids Symposium Series 2000Searching for more effective anti-HIV agents, we have prepared 4'-ethynyl-purine nucleosides. They were derived in several steps from 4-C-triethylsilylethynyl ribose,...
Searching for more effective anti-HIV agents, we have prepared 4'-ethynyl-purine nucleosides. They were derived in several steps from 4-C-triethylsilylethynyl ribose, which was used as an intermediate in the synthesis of pyrimidine nucleosides. The adenine derivative exhibited significant anti-HIV activity and favorable cytotoxicity profile in vitro.
Topics: Anti-HIV Agents; Cell Death; Cell Line; Drug Design; HIV; Humans; In Vitro Techniques; Methods; Purine Nucleosides; Structure-Activity Relationship
PubMed: 12903290
DOI: 10.1093/nass/44.1.105 -
Journal of Biotechnology Apr 1990A sensitive and highly selective method for the simultaneous determination of purine bases and their nucleosides is proposed. An amperometric flow-injection system with...
A sensitive and highly selective method for the simultaneous determination of purine bases and their nucleosides is proposed. An amperometric flow-injection system with the two immobilized enzyme reactors (guanase immobilized reactor and purine nucleoside phosphorylase/xanthine oxidase co-immobilized reactor) is used as the specific post-column detection system of HPLC, to convert compounds separated by a reversed-phase. HPLC column to electroactive species (hydrogen peroxide and uric acid) which can be detected at a flow-through platinum electrode. The proposed detection system is specific for a group of purine bases and purine nucleosides and does not respond for purine nucleotides and pyrimidine bases. The linear determination ranges are from 10 pmol to 5 nmol for four purine bases (hypoxanthine, xanthine, guanine, and adenine) and four purine nucleosides (inosine, xanthosine, guanosine, and adenosine). The detection limits are 1.2-5.5 pmol.
Topics: Chromatography, High Pressure Liquid; Enzymes, Immobilized; Guanine Deaminase; Hydrogen-Ion Concentration; Purine Nucleosides; Purine-Nucleoside Phosphorylase; Purines; Xanthine Oxidase
PubMed: 1367430
DOI: 10.1016/0168-1656(90)90021-3 -
The Journal of Organic Chemistry May 2015A modular and scalable approach to pyrimidine- and purine-containing constrained ethyl (cEt) nucleosides is demonstrated. Minimizing stereochemical adjustments and...
A modular and scalable approach to pyrimidine- and purine-containing constrained ethyl (cEt) nucleosides is demonstrated. Minimizing stereochemical adjustments and protecting group manipulations, diacetone glucose is converted to two representative cEt nucleosides via a functionalized, common intermediate. The retrosynthetic approach to this complex class of drug precursors offers clear benefits over existing routes based on step count and efficiency.
Topics: Molecular Structure; Nucleosides; Prodrugs; Purine Nucleosides; Pyrimidine Nucleosides
PubMed: 25894018
DOI: 10.1021/acs.joc.5b00607