Abstract
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.
Highlights
Medicinal applications of fluorinated drugs continue to expand rapidly, in part because of new developments in fluorine chemistry that extend the range of compounds that can readily be prepared with fluorine substitution, and because of the increased understanding of how biological and biochemical processes are uniquely perturbed by fluorine substitution
5-fluoro-20 -deoxyuridine-50 -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
Capitalizing on the increased uptake of uracil by some malignant cells, Heidelberger developed fluorinated pyrimidines (FPs) [2], and showed that 5-fluorouracil (5-FU) is metabolized to compounds that are highly cytotoxic to a variety of cells including cancer cells [3]
Summary
Medicinal applications of fluorinated drugs continue to expand rapidly, in part because of new developments in fluorine chemistry that extend the range of compounds that can readily be prepared with fluorine substitution, and because of the increased understanding of how biological and biochemical processes are uniquely perturbed by fluorine substitution. The strength of the C–F bond is critical to FdUMP inhibiting thymidylate synthase (TS), as dUMP analogs that include halogens with weaker C–X bonds undergo dehalogenation by TS, while FdUMP remains stably bound inhibiting further enzymatic activity. A key concept in the use of fluorinated analogs of native metabolites is lethal synthesis [1]. To undergo thymineless cancer cells reliant on the de novo thymidylate pathway to undergo thymineless death [7]. RNA-mediated processes perturbed by RNA remains an active of research. The discovery of specific RNA-mediated processes perturbed by RNA remains anarea active area of. In this regard, potential roles new for RNA enzymes perturbed by 5-FU [14], research.
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