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Chemistry of Fluorinated Pyrimidines in the Era of Personalized Medicine
We review developments in fluorine chemistry contributing to the more precise use of fluorinated pyrimidines (FPs) to treat cancer. 5-Fluorouracil (5-FU) is the most widely used FP and is used to treat > 2 million cancer patients each year. We review methods for 5-FU synthesis, including the inco...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435603/ https://www.ncbi.nlm.nih.gov/pubmed/32751071 http://dx.doi.org/10.3390/molecules25153438 |
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author | Gmeiner, William H. |
author_facet | Gmeiner, William H. |
author_sort | Gmeiner, William H. |
collection | PubMed |
description | We review developments in fluorine chemistry contributing to the more precise use of fluorinated pyrimidines (FPs) to treat cancer. 5-Fluorouracil (5-FU) is the most widely used FP and is used to treat > 2 million cancer patients each year. We review methods for 5-FU synthesis, including the incorporation of radioactive and stable isotopes to study 5-FU metabolism and biodistribution. We also review methods for preparing RNA and DNA substituted with FPs for biophysical and mechanistic studies. New insights into how FPs perturb nucleic acid structure and dynamics has resulted from both computational and experimental studies, and we summarize recent results. Beyond the well-established role for inhibiting thymidylate synthase (TS) by the 5-FU metabolite 5-fluoro-2′-deoxyuridine-5′-O-monophosphate (FdUMP), recent studies have implicated new roles for RNA modifying enzymes that are inhibited by 5-FU substitution including tRNA methyltransferase 2 homolog A (TRMT2A) and pseudouridylate synthase in 5-FU cytotoxicity. Furthermore, enzymes not previously implicated in FP activity, including DNA topoisomerase 1 (Top1), were established as mediating FP anti-tumor activity. We review recent literature summarizing the mechanisms by which 5-FU inhibits RNA- and DNA-modifying enzymes and describe the use of polymeric FPs that may enable the more precise use of FPs for cancer treatment in the era of personalized medicine. |
format | Online Article Text |
id | pubmed-7435603 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-74356032020-08-28 Chemistry of Fluorinated Pyrimidines in the Era of Personalized Medicine Gmeiner, William H. Molecules Review We review developments in fluorine chemistry contributing to the more precise use of fluorinated pyrimidines (FPs) to treat cancer. 5-Fluorouracil (5-FU) is the most widely used FP and is used to treat > 2 million cancer patients each year. We review methods for 5-FU synthesis, including the incorporation of radioactive and stable isotopes to study 5-FU metabolism and biodistribution. We also review methods for preparing RNA and DNA substituted with FPs for biophysical and mechanistic studies. New insights into how FPs perturb nucleic acid structure and dynamics has resulted from both computational and experimental studies, and we summarize recent results. Beyond the well-established role for inhibiting thymidylate synthase (TS) by the 5-FU metabolite 5-fluoro-2′-deoxyuridine-5′-O-monophosphate (FdUMP), recent studies have implicated new roles for RNA modifying enzymes that are inhibited by 5-FU substitution including tRNA methyltransferase 2 homolog A (TRMT2A) and pseudouridylate synthase in 5-FU cytotoxicity. Furthermore, enzymes not previously implicated in FP activity, including DNA topoisomerase 1 (Top1), were established as mediating FP anti-tumor activity. We review recent literature summarizing the mechanisms by which 5-FU inhibits RNA- and DNA-modifying enzymes and describe the use of polymeric FPs that may enable the more precise use of FPs for cancer treatment in the era of personalized medicine. MDPI 2020-07-29 /pmc/articles/PMC7435603/ /pubmed/32751071 http://dx.doi.org/10.3390/molecules25153438 Text en © 2020 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Gmeiner, William H. Chemistry of Fluorinated Pyrimidines in the Era of Personalized Medicine |
title | Chemistry of Fluorinated Pyrimidines in the Era of Personalized Medicine |
title_full | Chemistry of Fluorinated Pyrimidines in the Era of Personalized Medicine |
title_fullStr | Chemistry of Fluorinated Pyrimidines in the Era of Personalized Medicine |
title_full_unstemmed | Chemistry of Fluorinated Pyrimidines in the Era of Personalized Medicine |
title_short | Chemistry of Fluorinated Pyrimidines in the Era of Personalized Medicine |
title_sort | chemistry of fluorinated pyrimidines in the era of personalized medicine |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435603/ https://www.ncbi.nlm.nih.gov/pubmed/32751071 http://dx.doi.org/10.3390/molecules25153438 |
work_keys_str_mv | AT gmeinerwilliamh chemistryoffluorinatedpyrimidinesintheeraofpersonalizedmedicine |