The Photochemistry of 5-Fluorouracil<sup>*</sup><sup>†</sup>

Lozeron, Homer A.; Gordon, Milton P.; Gabriel, Thomas F.; Tautz, William; Duschinsky, Robert

doi:10.1021/bi00900a009

Cited by 46 publications

(16 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In other words, the similar kinetics argue that the relative quantum yields of CPD and photohydrate formation in dXpdX are similar to those of dUpdU and significantly different from those of dTpdT. It is interesting to note that the photochemistry of 5-fluorouracil appears to be independent of the length of the polynucleoside or the length of the chain connecting the 5-fluorouracil nucleobases, as all 5-fluorouracil systems studied to date form predominantly the photohydrates (9)(10)(11). This result is in contrast to that seen with thymine and, to a lesser extent, uracil, where the quantum yields for CPD formation increase with increasing sequence length.…”

Section: Resultsmentioning

confidence: 93%

Photochemistry of 5‐Fluorouracil Dideoxyribonucleoside Monophosphate

Faichuk

Mah

Loppnow³

2007

Photochem & Photobiology

View full text Add to dashboard Cite

5-Fluorouracil is an artificial nucleobase analog of thymine and uracil, with a substituent in the 5-position that has a mass similar to the methyl group in thymine, but very different electronic, steric and vibrational coupling properties. UVC irradiation of 5-fluorouracil dideoxyribonucleoside monophosphate (dXpdX) is examined here with mass spectrometry and UV-Vis absorption spectroscopy and is compared to the UV photochemistry of other pyrimidine dideoxyribonucleoside monophosphates. The results show that the photochemical products and kinetics of dXpdX are similar to those of uracil dideoxyribonucleoside monophosphate and similar to those of the isolated 5-fluorouracil nucleobase. The photochemistry of dXpdX is compared to the photochemistry of thymine and uracil dideoxyribonucleoside monophosphates.

show abstract

Section: Resultsmentioning

confidence: 93%

Photochemistry of 5‐Fluorouracil Dideoxyribonucleoside Monophosphate

Faichuk

Mah

Loppnow³

2007

Photochem & Photobiology

View full text Add to dashboard Cite

show abstract

“…Synthesis of FHPA FUOH (6.7 mg, 45 ,umol) was dissolved in 12 ml of 1 M potassium hydroxide at ambient temperature and the mixture was stirred for 1 h (Lozeron et al, 1964). Sodium borohydride (2.3 mg, 60 gmol) was then added.…”

Section: Materials and Methods Chemicalsmentioning

confidence: 99%

“…Synthesis of FHPA FUOH (6.7 mg,45 ,umol) was dissolved in 12 ml of 1 M potassium hydroxide at ambient temperature and the mixture was stirred for 1 h (Lozeron et al, 1964 a 'F-NMR 6 are related to external trifluoroethanoic acid (5% (w/v) aqueous solution). bd, Doublet; t, triplet.…”

Section: Materials and Methods Chemicalsmentioning

confidence: 99%

“…5,6-Dihydro-6-hydroxy-5-fluorouracil (FUOH) was supplied by PCR, Gainesville, FL, USA. All other chemicals were reagent grade and obtained from standard commercial sources.Synthesis of FHPA FUOH (6.7 mg, 45 ,umol) was dissolved in 12 ml of 1 M potassium hydroxide at ambient temperature and the mixture was stirred for 1 h (Lozeron et al, 1964). Sodium borohydride (2.3 mg, 60 gmol) was then added.…”

mentioning

confidence: 99%

See 1 more Smart Citation

The anti-cancer drug 5-fluorouracil is metabolized by the isolated perfused rat liver and in rats into highly toxic fluoroacetate

Arellano

Mc²,

Martino³

et al. 1998

Br J Cancer

View full text Add to dashboard Cite

Summary We report the first demonstration of the biotransformation of the anti-cancer drug 5-fluorouracil (FU) into two new metabolites, a-fluoro-f-hydroxypropionic acid (FHPA) and fluoroacetate (FAC), in the isolated perfused rat liver (IPRL) and in the rat in vivo. IPRL was perfused with solutions of pure FU at two doses, 15 or 45 mg kg-' body weight, and rats were injected i.p. with 180 mg of FU kg-' body weight.Fluorine-19 NMR analysis of perfusates from IPRL and rat urine showed the presence of the normal metabolites of FU and low amounts of FHPA (0.4% or 0.1% of injected FU in perfusates from IPRL treated with 15 or 45 mg of FU kg-' body weight, respectively; 0.08% of the injected FU in rat urine) and FAC (0.1% or 0.03% of injected FU in perfusates from IPRL treated with 15 or 45 mg of FU kg-' body weight, respectively; 0.003% of the injected FU in rat urine). IPRL was also perfused with a solution of a-fluoro-i-alanine (FBAL) hydrochloride at 16.6 mg kg-' body weight dose equivalent to 15 mg of FU kg-' body weight. Low amounts of FHPA (0.2% of injected FBAL) and FAC (0.07%) were detected in perfusates, thus demonstrating that FHPA and FAC arise from FBAL catabolism. As FAC is a well-known cardiotoxic poison, and FHPA is also cardiotoxic at high doses, the cardiotoxicity of FU might stem from at least two sources. The first one, established in previous papers (Lemaire et al, 1992(Lemaire et al, , 1994, is the presence in commercial solutions of FU of degradation products of FU that are metabolized into FHPA and FAC; these are formed over time in the basic medium necessary to dissolve the drug. The second, demonstrated in the present study, is the metabolism of FU itself into the same compounds.Keywords: 5-fluorouracil; a-fluoro-J-alanine; '9F nuclear magnetic resonance; metabolism; fluoroacetate; a-fluoro-o-hydroxypropionic acid; isolated perfused rat liver; rat urine 5-Fluorouracil (FU) is widely used as an anti-tumour agent for treatment of solid tumours. Its chief side-effects are myelosuppression, diarrhoea, vomiting and mucositis. However, over the last decade, the number of reports of cardiotoxicity and neurotoxicity attributed to FU has rapidly increased, probably because of the use of higher doses in continuous perfusion (Moertel et al, 1964;Rezkalla et al, 1989;Moore et al, 1990;Gamelin et al, 1991; De Fomi et al, 1992;Robben et al, 1993;Anand, 1994). The precise biochemical mechanism underlying these two side-effects remains unclear, although several investigators have postulated, but never demonstrated experimentally, that FU might be transformed into fluoroacetate (FAC), a highly cardiotoxic and neurotoxic poison (Koenig and Patel, 1970;Okeda et al, 1990). FAC enters the Krebs cycle and is then transformed into fluorocitrate, which inhibits the enzyme aconitase. Aconitase catalyses the conversion of citrate to isocitrate via the obligatory intermediate cis-aconitate. Inhibition of aconitase leads to a build-up of citrate in animal tissues (in particular heart) and serum, and the heart product...

show abstract

“…Support for the slow formation of some ftuoromalonaldehydic acid from LXXXI derives by analogy with the studies of Lozeron et a[. 41 who had noted that 5,6-dihydro-5-ftuoro-6-hydroxyuracil is converted in alkali to urea and ftuoromalonaldehydic acid. Conceivably, this latter type of degradation could also occur with the 5-bromo analogue.…”

mentioning

confidence: 69%

Pyrimidine nucleoside transformations via anhydronucleoside

Fox¹

1969

Pure and Applied Chemistry

View full text Add to dashboard Cite

The field of nucleosides has undergone rapid growth and development during the past decadel-3, Whereas, earlier studies were concerned with the development of methods for the synthesis of the nucleoside components of the nucleic acids, today several methods are available-each of which has its advantages and limitations. The host of "fraudulent" or "anomalous" nucleosides available today attests to the ability of chemists to cope with this interesting and rather complex group of compounds. Nor have their efforts been unrewarding. It is obvious to all that nucleosides have provided their fair share ofinteresting biochemieals useful in the elucidation ofbiosynthetic pathways and helpful both as anti-neoplastic and anti-viral agents. In addition, the increasing amount of "odd" nucleosides found as minor components of certain nucleic acids4, especially of transfer RNA, has further stimulated chemical efforts .in this area. Finally, the continuing discovery ofnucleoside antibiotics5 (ofwhich there are now over twenty) has served to introduce an increasing nurober of natural-products chemists into this burgeoning field.This discussion deals with but one aspect of our research during the past few years in the area of the pyrimidine n ucleosides and is not in tended as a comprehensive review. Specifically, it covers that aspect of our endeavours involved in the use of preformed nucleosides, natural or anomalous, as precursor~ for the synthesis of new nucleosides. As with most workers in this area, our studies are motivated by biochemical or biological interests, and reference to such considerations will be made in this discussion.Nucleoside chemistry is replete with examples from many laboratories of nucleoside transformations which involved alteration only of the aglycon portion, that is, reactions in which the sugar moiety played a "passive" role. Halogenation, methylation, thiation, deamination, etc. of the main nucleosides of the nucleic acids ( Figure 1) and of others are well documentedl-3. Our main interest however was in alterations in the carbohydrate moieties of nucleosides. One of the significant developments in nucleoside chemistry was the earlier discoveries 6 by Brown, Michelson, Todd and their associates at Cambridge who showed that pyrimidine anhydronucleosides ( or "cyclonucleosides") could be formed which involve an oxygen bridge between carbon-2 of the aglycon and the sugar moiety. We will discuss the chernistry of these and other types of anhydronucleosides as tools for stereochemically-controlled reactions involving:(a) alteration of the configuration of the sugar moiety;

show abstract

The Photochemistry of 5-Fluorouracil^*^†

Cited by 46 publications

References 12 publications

Photochemistry of 5‐Fluorouracil Dideoxyribonucleoside Monophosphate

Photochemistry of 5‐Fluorouracil Dideoxyribonucleoside Monophosphate

The anti-cancer drug 5-fluorouracil is metabolized by the isolated perfused rat liver and in rats into highly toxic fluoroacetate

Pyrimidine nucleoside transformations via anhydronucleoside

Contact Info

Product

Resources

About

The Photochemistry of 5-Fluorouracil*†

Cited by 46 publications

References 12 publications

Photochemistry of 5‐Fluorouracil Dideoxyribonucleoside Monophosphate

Photochemistry of 5‐Fluorouracil Dideoxyribonucleoside Monophosphate

The anti-cancer drug 5-fluorouracil is metabolized by the isolated perfused rat liver and in rats into highly toxic fluoroacetate

Pyrimidine nucleoside transformations via anhydronucleoside

Contact Info

Product

Resources

About

The Photochemistry of 5-Fluorouracil^*^†