Nucleic acid related compounds. 21. Direct fluorination of uracil and cytosine bases and nucleosides using trifluoromethyl hypofluorite. Mechanism, stereochemistry, and synthetic applications

Robins, Morris J.; MacCoss, Malcolm; Naik, S. R.; Ramani, Gautam

doi:10.1021/ja00439a046

Cited by 76 publications

(17 citation statements)

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“…In 1957, a synthesis of 5-FU 2 was reported in which the compound was prepared from pseudourea salts and α-fluoro-β-keto ester enolates. − Twenty years later, Robins et al reported a two-step synthesis of 5-FU 2 from uracil 18 (Scheme ). Trifluoromethyl hypofluorite was used to introduce a fluorine atom into the uracil ring, and the resulting fluorinated adduct 66 underwent base-catalyzed elimination of MeOH, generating 5-fluoro-pyrimidine 2 . An alternative synthesis used the cheap and readily available ortic acid (vitamin B13, 67 ) as the starting material .…”

Section: Pyrimidine Analogsmentioning

confidence: 99%

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

et al. 2016

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Nucleoside, nucleotide, and base analogs have been in the clinic for decades to treat both viral pathogens and neoplasms. More than 20% of patients on anticancer chemotherapy have been treated with one or more of these analogs. This review focuses on the chemical synthesis and biology of anticancer nucleoside, nucleotide, and base analogs that are FDA-approved and in clinical development since 2000. We highlight the cellular biology and clinical biology of analogs, drug resistance mechanisms, and compound specificity towards different cancer types. Furthermore, we explore analog syntheses as well as improved and scale-up syntheses. We conclude with a discussion on what might lie ahead for medicinal chemists, biologists, and physicians as they try to improve analog efficacy through prodrug strategies and drug combinations.

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Section: Pyrimidine Analogsmentioning

confidence: 99%

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

et al. 2016

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“…Previous syntheses of FdC report low yields, complexity of products, and the need for potentially toxic and explosive reagents (14)(15)(16). The difficulties in the synthesis have resulted in a reduced availability of FdC, posing a significant problem for the synthesis of FC-containing oligonucleotides using either unprotected FdC or N 4 -benzylated FdC.…”

Section: Introductionmentioning

confidence: 99%

¹⁵N-Enriched 5-Fluorocytosine as a Probe for Examining Unusual DNA Structures

Sowers

2000

Journal of Biomolecular Structure and Dynamics

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A new method is presented for the synthesis of oligonucleotides containing 15N-enriched 5-fluorocytosine (FC). Due to the reduced pK of FC, the amino protons of an unpaired FC residue may be observed at lower values of solution pH. The labeled FC residue has been placed as a template base at a model DNA replication fork. The amino protons of the FC residue have been identified in isotope-edited NMR spectra. Data is presented for a template FC residue unpaired, paired with guanine, and mispaired with adenine. These studies demonstrate the utility of labeled FC in examining unusual DNA structures.

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“…The location of the wide resonance (R) (4.4 ppm upfield to FU) is indicative for FU in short unstructured RNA (20–30 nt). Assignment of the minor signal (2′Om) to 2′- O -methyl-5-fluorouridine has been supported by inspection of MODOMICS database [40] against the spectral data for FU derivatives [41].…”

Section: Resultsmentioning

confidence: 99%

Combined in silico and 19F NMR analysis of 5-fluorouracil metabolism in yeast at low ATP conditions

et al. 2019

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The cytotoxic effect of 5-fluorouracil (5-FU) on yeast cells is thought to be mainly via a misincorporation of fluoropyrimidines into both RNA and DNA, not only DNA damage via inhibition of thymidylate synthase (TYMS) by fluorodeoxyuridine monophosphate (FdUMP). However, some studies on Saccharomyces cerevisiae show a drastic decrease in ATP concentration under oxidative stress, together with a decrease in concentration of other tri- and diphosphates. This raises a question if hydrolysis of 5-fluoro-2-deoxyuridine diphosphate (FdUDP) under oxidative stress could not lead to the presence of FdUMP and the activation of so-called ‘thymine-less death’ route. We attempted to answer this question with in silico modeling of 5-FU metabolic pathways, based on new experimental results, where the stages of intracellular metabolism of 5-FU in Saccharomyces cerevisiae were tracked by a combination of 19F and 31P NMR spectroscopic study. We have identified 5-FU, its nucleosides and nucleotides, and subsequent di- and/or triphosphates. Additionally, another wide 19F signal, assigned to fluorinated unstructured short RNA, has been also identified in the spectra. The concentration of individual metabolites was found to vary substantially within hours, however, the initial steady-state was preserved only for an hour, until the ATP concentration dropped by a half, which was monitored independently via 31P NMR spectra. After that, the catabolic process leading from triphosphates through monophosphates and nucleosides back to 5-FU was observed. These results imply careful design and interpretation of studies in 5-FU metabolism in yeast.

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Nucleic acid related compounds. 21. Direct fluorination of uracil and cytosine bases and nucleosides using trifluoromethyl hypofluorite. Mechanism, stereochemistry, and synthetic applications

Cited by 76 publications

References 3 publications

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

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

¹⁵N-Enriched 5-Fluorocytosine as a Probe for Examining Unusual DNA Structures

Combined in silico and 19F NMR analysis of 5-fluorouracil metabolism in yeast at low ATP conditions

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Nucleic acid related compounds. 21. Direct fluorination of uracil and cytosine bases and nucleosides using trifluoromethyl hypofluorite. Mechanism, stereochemistry, and synthetic applications

Cited by 76 publications

References 3 publications

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

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

15N-Enriched 5-Fluorocytosine as a Probe for Examining Unusual DNA Structures

Combined in silico and 19F NMR analysis of 5-fluorouracil metabolism in yeast at low ATP conditions

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¹⁵N-Enriched 5-Fluorocytosine as a Probe for Examining Unusual DNA Structures