scholarly journals 5-Fluorouracil—Complete Insight into Its Neutral and Ionised Forms

Molecules ◽  
2019 ◽  
Vol 24 (20) ◽  
pp. 3683 ◽  
Author(s):  
Justyna Wielińska ◽  
Andrzej Nowacki ◽  
Beata Liberek

5-Fluorouracil (5FU), a common anti-cancer drug, occurs in four tautomeric forms and possesses two potential sites of both protonation and deprotonation. Tautomeric and resonance structures of the ionized forms of 5FU create the systems of connected equilibriums. Since there are contradictory reports on the ionized forms of 5FU in the literature, complex theoretical studies on neutral, protonated and deprotonated forms of 5FU, based on the broad spectrum of DFT methods, are presented. These indicate that the O4 oxygen is more willingly protonated than the O2 oxygen and the N1 nitrogen is more willingly deprotonated than the N3 nitrogen in a gas phase. Such preferences are due to advantageous charge delocalization of the respective ions, which is demonstrated by the NBO and ESP analyses. In an aqueous phase, stability differences between respective protonated and deprotonated forms of 5FU are significantly diminished due to the competition between the mesomeric effect and solvation. The calculated pKa values of the protonated, neutral and singly deprotonated 5FU indicate that 5FU does not exist in the protonated and double-deprotonated forms in the pH range of 0–14. The neutral form dominates below pH 8 and the N1 deprotonated form dominates above pH 8.

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 788 ◽  
Author(s):  
William H. Gmeiner ◽  
Lance D. Miller ◽  
Jeff W. Chou ◽  
Anthony Dominijanni ◽  
Lysette Mutkus ◽  
...  

Chemo-immunotherapy is central to the treatment of small cell lung cancer (SCLC). Despite modest progress made with the addition of immunotherapy, current cytotoxic regimens display minimal survival benefit and new treatments are needed. Thymidylate synthase (TS) is a well-validated anti-cancer drug target, but conventional TS inhibitors display limited clinical efficacy in refractory or recurrent SCLC. We performed RNA-Seq analysis to identify gene expression changes in SCLC biopsy samples to provide mechanistic insight into the potential utility of targeting pyrimidine biosynthesis to treat SCLC. We identified systematic dysregulation of pyrimidine biosynthesis, including elevated TYMS expression that likely contributes to the lack of efficacy for current TS inhibitors in SCLC. We also identified E2F1-3 upregulation in SCLC as a potential driver of TYMS expression that may contribute to tumor aggressiveness. To test if TS inhibition could be a viable strategy for SCLC treatment, we developed patient-derived organoids (PDOs) from human SCLC biopsy samples and used these to evaluate both conventional fluoropyrimidine drugs (e.g., 5-fluorouracil), platinum-based drugs, and CF10, a novel fluoropyrimidine polymer with enhanced TS inhibition activity. PDOs were relatively resistant to 5-FU and while moderately sensitive to the front-line agent cisplatin, were relatively more sensitive to CF10. Our studies demonstrate dysregulated pyrimidine biosynthesis contributes to drug resistance in SCLC and indicate that a novel approach to target these pathways may improve outcomes.


2005 ◽  
Vol 39 (11) ◽  
pp. 1147-1154 ◽  
Author(s):  
Gururaj Joshi ◽  
Rukhsana Sultana ◽  
Jitbanjong Tangpong ◽  
Marsha Paulette Cole ◽  
Daret K. St Clair ◽  
...  

Xenobiotica ◽  
2009 ◽  
Vol 00 (00) ◽  
pp. 090901052053001-8
Author(s):  
K. Murai ◽  
H. Yamazaki ◽  
K. Nakagawa ◽  
R. Kawai ◽  
T. Kamataki

2010 ◽  
Author(s):  
N. Magnavita ◽  
I. lavicoli ◽  
V. Leso ◽  
A. Bergamaschi

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