Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs

Shelton, Jadd R.; Lu, Xiao; Hollenbaugh, Joseph A.; Cho, Jong Hyun; Amblard, Franck; Schinazi, Raymond F.

doi:10.1021/acs.chemrev.6b00209

Cited by 317 publications

(287 citation statements)

References 660 publications

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“…15,16 The triphosphates are inhibitors of DNA or RNA polymerases, preferably with specificity for the targeted organism. Nucleoside analogues missing the ribosyl 3′-hydroxyl group are chain terminators of nucleic acid synthesis.…”

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confidence: 99%

Immucillins in Infectious Diseases

2017

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The Immucillins are chemically stable analogues that mimic the ribocation and leaving-group features of N-ribosyltransferase transition states. Infectious disease agents often rely on ribosyltransferase chemistry in pathways involving precursor synthesis for nucleic acids, salvage of nucleic acid precursors, or synthetic pathways with nucleoside intermediates. Here, we review three infectious agents and the use of the Immucillins to taget enzymes essential to the parasites. First, DADMe-Immucillin-G is a purine nucleoside phosphorylase (PNP) inhibitor that blocks purine salvage and shows clinical potential for treatment for the malaria parasite Plasmodium falciparum, a purine auxotroph requiring hypoxanthine for purine nucleotide synthesis. Inhibition of the PNPs in the host and in parasite cells leads to apurinic starvation and death. Second, Helicobacter pylori, a causative agent of human ulcers, synthesizes menaquinone, an essential electron transfer agent, in a pathway requiring aminofutalosine nucleoside hydrolysis. Inhibitors of the H. pylori methylthioadenosine nucleosidase (MTAN) are powerful antibiotics for this organism. Synthesis of menaquinone by the aminofutalosine pathway does not occur in most bacteria populating the human gut microbiome. Thus, MTAN inhibitors provide high-specificity antibiotics for H. pylori and are not expected to disrupt the normal gut bacterial flora. Third, Immucillin-A was designed as a transition state analogue of the atypical PNP from Trichomonas vaginalis. In antiviral screens, Immucillin-A was shown to act as a prodrug. It is active against filoviruses and flaviviruses. In virus-infected cells, Immucillin-A is converted to the triphosphate, is incorporated into the viral transcript, and functions as an atypical chain-terminator for RNA-dependent RNA polymerases. Immucillin-A has entered clinical trials for use as an antiviral. We also summarize other Immucillins that have been characterized in successful clinical trials for T-cell lymphoma and gout. The human trials support the potential development of the Immucillins in infectious diseases.

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confidence: 99%

Immucillins in Infectious Diseases

2017

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“…First the fully-protected sugar (26) is brominated to form the 1-α-glycosyl bromide (27), formation of which leads preferentially to the formation of β-nucleoside (28) as reported in the synthesis of the antineoplastic agent clofarabine (6) ( Figure 9) [19]. Schinazi et al [22].…”

Section: N-glycosylation Of Fluorine-containing Starting Materialsmentioning

confidence: 95%

Fluorinated Nucleosides as an Important Class of Anticancer and Antiviral Agents

et al. 2017

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Fluorine-containing nucleoside analogues represent a significant class of FDA approved chemotherapeutics widely used in the clinic. The incorporation of fluorine into drug-like agents modulates lipophilic, electronic and steric parameters thus influencing pharmacodynamic and pharmacokinetic properties of drugs. Fluorine can block oxidative metabolism of drugs and the formation of undesired metabolites by changing H-bonding interactions. In this review, we focus our attention on chemical fluorination reagents and methods used in the nucleoside analogues field, including PET radiochemistry. We briefly discuss both the cellular biology and clinical properties of FDA-approved and fluorine-containing nucleoside/nucleotide analogues in development as well as common resistance mechanisms associated with their use. Finally, we emphasize pro-nucleotide strategies used to improve therapeutic outcome of nucleoside analogues in the clinic.

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“…Their incorporation into DNA chain causes demethylation and hypomethylation of fragments. Moreover, some nucleoside drugs can show activation of apoptosis routes on cytoplasm and mitochondrial side …”

Section: Introductionmentioning

confidence: 99%

“…Anticancer nucleosides present numerous pharmacokinetic problems, such as low selectivity in attacking cancer cells, and an extracellular inactivation and degradation due to their high chemical and biological lability. They also show very pharmacodynamics disadvantages, some of these are as follows: low cellular uptake, intracellular inactivation and biological degradation by means of ecto‐nucleotidase and nucleoside deaminase enzymes . Due to the great disadvantages revealed, the nucleoside drugs have a very short plasma half‐life and very low oral bioavailability; therefore, these drugs type should be administered in higher doses and intravenously to be effective.…”

Section: Introductionmentioning

confidence: 99%

Anomalous interaction of tri-acyl ester derivatives of uridine nucleoside with a l-α-dimyristoylphosphatidylcholine biomembrane model: a differential scanning calorimetry study

Escobar

Fernández

Giordani

et al. 2019

Journal of Pharmacy and Pharmacology

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Objectives Uridine was conjugated with fatty acids to improve the drug lipophilicity and the interaction with phospholipid bilayers. Methods The esterification reaction using carbodiimides compounds as coupling agents and a nucleophilic catalyst allowed us to synthesize tri‐acyl ester derivatives of uridine with fatty acids. Analysis of molecular interactions between these tri‐acyl ester derivatives and l‐α‐dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles (MLV) – as a mammalian cell membrane model – have been performed by differential scanning calorimetry (DSC). Key findings The DSC thermograms suggest that nucleoside and uridine triacetate softly interact with phospholipidic multilamellar vesicles which are predominantly located between the polar phase, whereas the tri‐acyl ester derivatives with fatty acids (myristic and stearic acids) present a strongly interaction with the DMPC bilayer due to the nucleoside and aliphatic chains parts which are oriented towards the polar and lipophilic phases of the phospholipidic bilayer, respectively. However, the effects caused by the tri‐myristoyl uridine and tri‐stearoyl uridine are different. Conclusions We show how the structural changes of uridine modulate the calorimetric behaviour of DMPC shedding light on their affinity with the phospholipidic biomembrane model.

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Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs

Cited by 317 publications

References 660 publications

Immucillins in Infectious Diseases

Immucillins in Infectious Diseases

Fluorinated Nucleosides as an Important Class of Anticancer and Antiviral Agents

Anomalous interaction of tri-acyl ester derivatives of uridine nucleoside with a l-α-dimyristoylphosphatidylcholine biomembrane model: a differential scanning calorimetry study

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