Uracil analogs 5-fluorouracil

Fluorouracil (5-fluorouracil, 5-FU, Fig. 5) represents an early example of rational drag design in that it originated from the observation that tumor cells, especially from gut, incorporate radiolabeled uracil more efficiently into DNA than normal cells. 5-FU is a fluorinated pyrimidine analog that must be activated metabolically. In the cells 5-FU is converted to 5-fluoro-2>deoxyuridine-monophosphate (FdUMP). This metabolite inhibits thymidilate synthase which catalyses the conversion of uridylate (dUMP) to thymidilate (dTMP) whereby methylenetetrahydrofo-late plays the role of the carbon-donating cofactor. The reduced folate cofactor occupies an allosteric site of... 

An interesting dinically useful prodrug is 5-fluorouracil, which is converted in vivo to 5-fluoro-2 -deoxyuridine 5 -monophosphate, a potent irreversible inactivator of thymidylate synthase It is sometimes charaderized as a dead end inactivator rather than a suicide substrate since no electrophile is unmasked during attempted catalytic turnover. Rathei since a fluorine atom replaces the proton found on the normal substrate enzyme-catalyzed deprotonation at the 5 -position of uracil cannot occur. The enzyme-inactivator covalent addud (analogous to the normal enzyme-substrate covalent intermediate) therefore cannot break down and has reached a dead end (R. R. Rando, Mechanism-Based Enzyme Inadivators , Pharm. Rev. 1984,36,111-142). 

The photoaddition of water to a variety of naturally occurring pyrimidine derivatives has been reported. Photolysis in aqueous solution of uracil (224 R = H), uridine (224 R=ribosyl), and uridylic acid results in the formation of the corresponding 6-hydroxy-5,6-dihydropyrimidine (225)208-210 these structures have been established by independent synthesis.209 Analogous photoadditions have been observed in 1,3-dimethyluracil211 and 5-fluorouracil.212 These additions are reversible. 

Fluorouracil [flure oh YOOR a sil] (5-FU), a pyrimidine analog, has a stable fluorine atom in place of a hydrogen atom at position 5 of the uracil ring. The fluorine interferes with the conversion of deoxyuridylic acid to thymidylic acid, thus depriving the cell of one of the essential precursors for DNA synthesis. 

Uracil undergoes addition of trifluoromethyl hypofluorite at — 78 CC and this adduct reacts with triethylamine to give 5-fluorouracil (13, X = O R = H).396 Other 5-fluorouracil derivatives 13, important fluoronucleic bases and fluoronucleosides, can be prepared in an analogous... 

Fluorouracil (5-FU) is a fluorinated analog of the naturally occurring pyrimidine uracil, originally synthesized in the late 1950s (Table 124—11). It is a prodrug and must be metabolized to the nucleotide form, fluorodeoxyuridine monophosphate (FdUMP), to be active. In the presence of folates, FdUMP binds tightly to and interferes with... 

Fluorouracil is catabolized in an analogous manner to uracil, forming the following degradative products dihydrofluorouraci1, a-fluoro-6-ureidopropionic acid, a-fluoro-3-guanidopropionic acid, a-fluoro-3-alanine, urea, and CO2 (16). 

Leishmarual UPRT is a unique en mie that, while probably not essential, could potentially be subverted to selectively metabolize toxic pyrimidine analogs. Identifying analog selective toxic to Leishmania could be challenging, as evidenced 1 the toxicity of the UPRT substrate 3-fluorouracil to both IMshmania and humans. While humans la UPRT, they incorporate 5-fluotouracil into the nucleotide pool via alternative mechanisms mechanisms that must be bypassed for any uracil analt to demonstrate sdective toxicity. 

Water soluble nucleic acid analogs were prepared by grafting uracil, thymine, 5-fluorouracil, hypoxanthine, cytosine, and adenine derivatives containing a hydroxy group onto linear poly(ethyleneimine). These polymers contained about 90 unit% of the nucleic acid bases, and were easily soluble in water at neutral pH resign. The analogs were found to form complementary polymer complexes with each other and with polynucleotides. The interaction study was made on these polymers, and with polynucleotides poly(uridylic acid) poly(U), poly(adenylic acid) poly(A), poly(inosinic acid) poly(I) and poly(cytidylic acid) poly(C) in water. They were found to form polymer complexes with polynucleotide by specific base-base interaction in aqueous solution. 

In the present study, water soluble poly(ethyleneimine) derivatives containing uracil, thymine, 5-fluorouracil, hypoxanthine, cytosine, and adenine were prepared and their interactions with polynucleotides, such as poly(A), poly(U), poly(C), poly(I) in natural aqueous solution were investigated. As 5-fluorouracil is known as a famous anticancer agent, it seems to be interest to study the interaction of the polymer containing 5-fluorouracil unit with polynucleotides. The bioactivity of the polymer complex of nucleic acid analogs with polynucleotides will be reported... 

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