Structural, energetic and spectroscopic characterisation of 5-fluorouracil anticarcinogenic drug isomers, tautomers and ions

Othmani, H.; Said, Ridha Ben; Terzi, N.; Jaı̈dane, N.; Mogren, Muneerah Mogren Al; El‐Marghany, Adel; Hochlaf, M.

doi:10.1080/00268976.2018.1548715

Cited by 9 publications

(7 citation statements)

References 52 publications

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“…The computational results using B3LYP/def2-TZVP prove to be much more consistent with experimental results, with only a modest discrepancy of 1–2 kcal mol –1 when compared to experimental data (Table ). Comparison of our data to prior calculations (none of which used the def2-TZVP basis set) also indicates the improved accuracy of the B3LYP/def2-TZVP basis set and method for the halouracils. ,− …”

Section: Discussionsupporting

confidence: 51%

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Gas-Phase Experimental and Computational Studies of 5-Halouracils: Intrinsic Properties and Biological Implications

Krajewski

Lee

2021

J. Org. Chem.

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The gas-phase acidity and proton affinity (PA) of 5-halouracils (5-fluorouracil, 5-chlorouracil, 5-bromouracil, and 5-iodouracil) have been examined using both theoretical and experimental methods. This work represents a comprehensive study of the thermochemical properties of these nucleobases. Other than 5-fluorouracil acidity, the intrinsic acidity and PA of these halouracils have not been heretofore measured; these new experimental data provide a benchmark for the computational values. Furthermore, we examine these 5-halouracils in the context of the enzyme thymine DNA glycosylase (TDG), which is an enzyme that protects the genome by cleaving these substrates from DNA. Our gas-phase results are compared and contrasted to TDG excision rates to afford insights into the TDG mechanism.

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Section: Discussionsupporting

confidence: 51%

“…In this work, we examine the properties of halogenated uracils. 5-Halouracils (5XU, 1–4 ) are an intriguing class of compounds; such species are cytotoxic yet also have antitumor characteristics, with 5-fluorouracil (5FU, 1 ) being widely used in chemotherapy. − …”

Section: Introductionmentioning

confidence: 99%

Gas-Phase Experimental and Computational Studies of 5-Halouracils: Intrinsic Properties and Biological Implications

Krajewski

Lee

2021

J. Org. Chem.

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“…Thus, 5-FU base pairs are anticipated to be more dynamic and potentially contribute less to nucleic acid stability than native base pairs. Furthermore, in its neutral form, the keto-enol tautomer distribution of 5-FU [ 87 ] differs from Ura due to fluorine electronegativity [ 88 , 89 ], which may affect base pair geometry, and indirectly affects base stacking, which is a predominate force in duplex stability [ 90 ]. The net effects of FUrd substitution in RNA and FdU substitution in DNA were found to depend on both the site of substitution and how many sites were substituted.…”

Section: Synthesis Of 5-fu Substituted Rna and Dna For Biophysicalmentioning

confidence: 99%

Chemistry of Fluorinated Pyrimidines in the Era of Personalized Medicine

Gmeiner

2020

Molecules

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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.

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“…Pyrimidine bases, including uracil and its 5‐halogen derivatives, can exist in several tautomeric forms as free molecules and in polar solution. [ 21–26 ] Early theoretical studies on 5FU concentrated mainly on structure, tautomeric equilibria, and discrete hydration with several water molecules, using relatively low level ab initio (Hartree‐Fock and MP2) or density functional theory (DFT) calculations combined with fairly small Pople‐type basis sets. [ 27–30 ] Of six possible tautomers predicted in the gas phase and solution, the keto (K) and enol (E) forms shown in Figure 1 are the most stable ones.…”

Section: Introductionmentioning

confidence: 99%

Interaction of 5‐fluorouracil with β‐cyclodextrin: A density functional theory study with dispersion correction

Buczek

Staś

Hebenstreit

et al. 2020

Int J of Quantum Chemistry

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Detailed studies on the stability, interaction, and microstructure of host‐guest complexes in the vacuum of 5‐fluorouracil (5FU) with β‐cyclodextrin (βCD) were performed using B3LYP with the inclusion of Grimme's dispersion correction GD3 term and 6‐31+G(d,p) basis set. Among several studied 1:1 5FU‐βCD complexes, the one placing the keto tautomer of 5FU vertically in the host cavity and forming N‐H···OCD and CO···HOCD hydrogen bonds with hydroxyl groups of the smaller rim of βCD has the highest stability (Eint = −195 kJ/mol). Interestingly, there are no interactions with the inner hydrophobic part of the βCD host cavity. The strength of the intermolecular H‐bonds to the smaller rim of βCD is comparable to those in 5FU‐water and 5FU‐methanol clusters, used as model systems characterizing the noncovalent interactions. Of several studied host‐guest complexes, the inner ones are more stable than the outer systems. Our results reveal that taking dispersion interaction in DFT into account is essential for reliable modeling of the structure, interaction, and stability of 5FU‐βCD complexes. This study is crucial for understanding the interaction of 5FU with βCD in the solid state and additionally suggests the presence of equilibrium between 5FU‐βCD complex and solvated 5FU.

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Structural, energetic and spectroscopic characterisation of 5-fluorouracil anticarcinogenic drug isomers, tautomers and ions

Cited by 9 publications

References 52 publications

Gas-Phase Experimental and Computational Studies of 5-Halouracils: Intrinsic Properties and Biological Implications

Gas-Phase Experimental and Computational Studies of 5-Halouracils: Intrinsic Properties and Biological Implications

Chemistry of Fluorinated Pyrimidines in the Era of Personalized Medicine

Interaction of 5‐fluorouracil with β‐cyclodextrin: A density functional theory study with dispersion correction

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