Pharmacological Modulation of Fluoropyrimidines

O’Connor, Owen A.

doi:10.1385/1-59259-864-1:133

Cited by 3 publications

(5 citation statements)

References 127 publications

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“…MP2/6-31++G**//MP2/6-31G** calculations were carried out for uracil, 1, and the 18 derivatives (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) shown in Figure 1 employing the Gaussian98 program. 13 The QTAIM atomic properties were calculated by using the program AIMPAC 14 on the above indicated charge densities.…”

Section: Computational and Geometrical Detailsmentioning

confidence: 99%

“…Uracil, one of the pyrimidine bases involved in nucleoside structure, displays an important role in the search of new antiviral and antitumoral therapies. , Previously, it has been found that when a uracil derivative is part of a nucleoside analogue (5/6-F/Cl- cis -1-(2-hydroxymethyl-4-cyclopentenyl)uracil), the electronic properties of the pentose and the base remain practically unmodified with respect to those of the isolated molecules . For this reason, studying the structural properties of the isolated uracil derivatives is even more important, since the properties observed for them can be taken as a good approximation of the properties when they are just fragments of a more complex system.…”

Section: Introductionmentioning

confidence: 99%

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On the Electron Donor and the Electrophilic Substitution Activating Abilities of Substituents in Uracil

Moa

Mosquera

2006

J. Phys. Chem. A

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QTAIM properties for uracil and 18 derivatives containing the substituents -NH(2), -OH, -OCH(3), -SH, -F, -Cl, -CH(3) -NO(2), and -Li in position 5 or 6 were computed on MP2/6-31++G//MP2/6-31G charge densities. The results indicate that -OH, -OCH(3), and -NH(2) groups are really retrieving charge from the ring. Also, the activating ability of the substituent groups, usually considered as the variation of electron population at the carbon where the electrophilic attack takes place, C, was studied. The study shows that the activating ability is reflected by the variation of pi charge or quadrupole moment at C, and also by the variation of the Laplacian of the charge density in the secondary charge concentration points around C (SCC-C). They indicate a similar, but not exactly equal, graduation of activating ability. The relative behavior of the substituents is basically the same as in benzene, though benzene has more tendency to concentrate charge in the SCC-C regions than uracil, where this tendency is larger for 6- than for 5-derivatives. sigma(+/-)(R) Taft parameters are found to display good correlations with the above indicated activating indexes. Finally, the resonance model predicts most of the main variations displayed by QTAIM atomic pi electron populations of derivatives with regard to uracil, but there are still some significant variations of the pi electron charge that it cannot predict.

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Section: Computational and Geometrical Detailsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

On the Electron Donor and the Electrophilic Substitution Activating Abilities of Substituents in Uracil

Moa

Mosquera

2006

J. Phys. Chem. A

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“…FU has been a mainstay of chemotherapy for colon cancer and other malignancies. Currently, it is frequently used in combination therapies with other genotoxic agents, such as oxaliplatin and irinotecan [ 2 ]. In this study, we report the novel and unexpected observation that the deoxyuridine analogs, hmUdR, hUdR and foUdR, synergistically enhance the sensitivity of a variety of cell lines derived from solid tumors but not cell lines from normal tissues to FU.…”

Section: Discussionmentioning

confidence: 99%

“…These include reducing dTTP levels by inhibition of thymidylate synthase, misincorporation of both dUTP and FdUTP during DNA replication and repair of misincorporated dUTP and FdUTP, misincorporation of FUTP into RNA and disruption of several aspects of RNA metabolism. Through its long history, the mechanism of action of FU has been studied extensively, and a number of derivatives and combination therapies with other types of therapeutics have been developed to improve its effectiveness [ 2 ]. Nevertheless these combination therapies often increase the risk of severe side effects limiting clinical application, and many tumor types exhibit a low response rate and/or rapidly acquire resistance [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Synergistic enhancement of 5-fluorouracil cytotoxicity by deoxyuridine analogs in cancer cells

et al. 2015

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5-Fluorouracil (FU) is a halogenated nucleobase analog that is widely used in chemotherapy. Here we show that 5-hydroxymethyl-2′-deoxyuridine (hmUdR) synergistically enhances the activity of FU in cell lines derived from solid tumors but not normal tissues. While the cytotoxicity of FU and hmUdR was not directly related to the amount of the modified bases incorporated into cellular DNA, incubation with this combination resulted in dramatic increase in the number of single strand breaks in replicating cancer cells, leading to NAD-depletion as consequence of poly(ADP-ribose) synthesis and S phase arrest. Cell death resulting from the base/nucleoside combination did not occur by apoptosis, autophagy or necroptosis. Instead, the cells die via necrosis as a result of NAD depletion. The FU-related nucleoside analog, 5-fluoro-2′-deoxyuridine, also displayed synergy with hmUdR, whereas hmUdR could not be replaced by 5-hydroxymethyluracil. Among other 5-modified deoxyuridine analogs tested, 5-formyl-2′-deoxyuridine and, to a lesser extent, 5-hydroxy-2′-deoxyuridine, also acted synergistically with FU, whereas 5-hydroxyethyl-2′-deoxyuridine did not. Together, our results have revealed an unexpected synergistic interaction between deoxyuridine analogs and FU in a cancer cell-specific manner, and suggest that these novel base/nucleoside combinations could be developed into improved FU-based chemotherapies.

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“…Unfortunately, 5-FU shows major drawbacks such as a short half-life, erratic bioavailability, and various undesired side effects [ 28 ]. Throughout its long history, different strategies have been developed to improve the clinical efficiency of 5-FU such as the synthesis of new derivatives, combination or conjugation with other types of drugs, and entrapment or binding to polymers [ 29 , 30 , 31 ]. On the other hand, coumarin is a privileged scaffold in medicinal chemistry due to its vast pharmacological attributes [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

In Vitro Antioxidant and Pancreatic Anticancer Activity of Novel 5-Fluorouracil-Coumarin Conjugates

et al. 2022

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Molecular hybridization consists of the combination of two or more non-identical pharmacophores in a single molecule. It has emerged as a promising strategy that allows the design of molecular frameworks with enhanced activity and affinity compared to their parent drugs. In this work, two novel hybrids that combine the well-known anticancer chemotherapeutic agent 5-fluorouracil with antioxidant coumarin derivatives have been synthesized and characterized by means of a copper-catalyzed azide-alkyne cycloaddition (CuAAC). The conjugates showed good antioxidant properties and a high tendency to aggregate and form stable nanoparticles in aqueous media, with regular shape and uniform size. These materials have proven to be preferential cytotoxic agents in vitro against human pancreatic cancer cells PANC-1, with an activity superior to free 5-fluorouracil. These results open up the possibility of exploiting the synergistic combination between 5-fluorouracil and coumarin derivatives and warrant further investigation of these hybrids as promising pancreatic anticancer agents.

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Pharmacological Modulation of Fluoropyrimidines

Cited by 3 publications

References 127 publications

On the Electron Donor and the Electrophilic Substitution Activating Abilities of Substituents in Uracil

On the Electron Donor and the Electrophilic Substitution Activating Abilities of Substituents in Uracil

Synergistic enhancement of 5-fluorouracil cytotoxicity by deoxyuridine analogs in cancer cells

In Vitro Antioxidant and Pancreatic Anticancer Activity of Novel 5-Fluorouracil-Coumarin Conjugates

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