Uracils base-catalyzed

Another example of based-catalyzed elimination in the 2-deoxy sugar series is that of l-[2-deoxy-3-0-(methylsulfonyl)-5-0-trityl-/3-D-eryMro-pentofuranosyl]uracil and 2, 3-anhydro-l-(2-deoxy-5- 0-trityl-/3-D-<. reo-pentofuranosyl) uracil, which, when treated with potassium ferf-butoxide in methyl sulfoxide, give a 70% yield of a 2,3-unsaturated nucleoside.28... 

Figure 11.7. Enzymatic events leading to removal of DNA damage. The various types of DNA damage are removed by the action of several families of DNA repair enzymes. The result, in many cases, is a region where part of one strand of the double-stranded helix is missing. The empty region is then filled in with new nucleotides in a reaction catalyzed by DNA polymerase. The sequential activities of uracil DNA glycosylase, AP endonuclease, and 2 -deoxyribophosphodi-esterase catal)rze the total removal of uracil residues, as shown. Uracil DNA glycosylase hydrolyzes the uracil base from the DNA. The other two enzymes catalyze the hydrolysis of a phos-phodiester bond, and then the complete removal of the sugar residue. (From Teebor, 1995.)...

Base-catalyzed displacement of the sulfonyloxy groups of a mixture of the protected 5-(2-deoxy-D-a//o-and 2-deoxy-D- /tro-pentitol-l-yl)uracils 937 took place by an intramolecular Sn2 mechanism and afforded the two pyranoside C-nucleosides 938 and 939 (78MI3) (Scheme 268). 

The required functionality is introduced into the 5 position of the uracil ring by hydroxymethylation of 2, 3 -isopropylideneuridine followed by oxidation of the hydroxymethyl derivative with active Mn02 to yield 5-formyl-2, 3 -isopropylideneuridine. The latter is converted into the mono- and triphosphate by conventional procedures. During the synthesis of the monophosphate by the method of Tener, a base-catalyzed anomerization occurs so that a mixture of the a- and j8-anomers of 5-formyluridine monophosphate is produced. After conversion to the triphosphate, the two anomeric triphosphates may be separated. 

An unusual method for the preparation of fluorinated uracil derivatives 962 relied by Shermolovich with co-workers on reaction of fluorinated sulphones 957 with sodium cyanate in presence of triethylamine, followed by acidification (Scheme 204) [595]. The mechanism of the reaction included base-catalyzed elimination of HF, followed by addition of two cyanate ions to the formed alkene 958. 

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). 

Bovine pancreatic ribonuclease catalyzes the hydrolysis of RNA by a two-step process in which a cyclic phosphate intermediate is formed (equation 16.35). The cyclization step is usually much faster than the subsequent hydrolysis, so the intermediate may be readily isolated. DNA is not hydrolyzed, as it lacks the 2 -hydroxyl group that is essential for this reaction. There is a strong specificity for the base B on the 3 side of the substrate to be a pyrimidine—uracil or cytosine. 

Figure 5.26. Complementarity between mRNA and DNA. The base sequence of mRNA (red) is the complement of that of the DNA template strand (blue). The sequence shown here is from the tryptophan operon, a segment of DNA containing the genes for five enzymes that catalyze the synthesis of tryptophan. The other strand of DNA (black) is called the coding strand because it has the same sequence as the RNA transcript except for thymine (T) in place of uracil (U).

The dUTPase reaction is very important because the DNA polymerases cannot distinguish dUTP from TTP and catalyze significant incorporation of dUMP into DNA when dUTP is present. Incorporation of the base U into DNA is not deleterious because all cells contain a uracil... 

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