Cytidine reduction

The decreased level of free inositol leads to a reduction in the rate of Ptdlns resynthesis and to the subsequent accumulation of cytidine mo-nophosphorylphosphatidate (CMP-PA), the cosubstrate for the resynthesis, and of the other lipid metabolites, phosphatidic acid (PA) and DAG... 

Catalytic reduction of cytidine in water over rhodium on alumina yields the tetrahydro derivative [l-(/3-D-ribofuranosyl)-4-aminotetrahydropyrimidin-2(l//)-one] and l-( 3-D-ribofuranosyl)tetrahydropyrimidin-2(l/0-one as the major products [680]. The former hydrolyses readily to give tetrahydrouridine,which is a potent inhibitor of human liver deaminase. The latter compound is also formed by sodium borohydride reduction of 5,6-dihydrouridine. 

Tezacitabine is synthesized from the cytidine protected at 4 -OH, 5 -OH and 4-NH2. Swern oxidation provides a ketone, which is converted to a gem-fluoro-sulfonyl olefin with the anion of sulfonylfluorophosphonate. Reduction of the sulfonyl group is achieved with BusSnH (Fig. 33) [92]. 

Dideoxyhexoses. Several bacterial antigenic determinants with the general structure of 3,6-dideoxyhexoses occur in the cell wall of Pasteurella and Salmonella strains. Most of the transformations reported so far occur as cytidine nucleotides (see Table I, References 15, 16, 17, 18, 19). Here, again the first step is the transformation of the cytidine diphospho-linked glucose into its corresponding 4-keto derivative. By at least two distinct steps, requiring NADPH, reduction to several different 3,6-dideoxyhexoses have been reported. One 3,6-dideoxyhexose CDP-tyvelose (3,6-dideoxy-D-arabino hexose) is formed by a specific 2-epimer-ase from CDP-paratose (24). 

Box HC (1977) Radiation effects ESR and ENDOR Analysis. Academic Press, New York Box HC, Budzinski EE (1975) Primary radiation damage in thymidine. J Chem Phys 62 197-199 Box HC, Potter WR, Budzinski EE (1975) The reduction of nucleotides by ionizing radiation Uridine 5 phosphate and cytidine 3 phosphate. J Chem Phys 62 3476-3478 Box HC, Budzinski EE, Freund HG, Evans MS, Patrzyc HB, Wallace JC, Maccubbin AE (1993) Vicinal lesions in X-irradiated DNA Int J Radiat Biol 64 261-263 Box HC, Freund HG, Budzinski EE, Wallace JC, Maccubbin AE (1995) Free radical-induced double base lesions. Radiat Res 141 91-94... 

Table I. Macroeoulometric determination of number of electrons transferred (n) and amount of NHj evolved during electrochemical reduction of pyrimidone-2, cytosine and cytidine...

In accordance with the foregoing, i.e. that substitution at Nt does not affect the reduction pathway, the nucleoside and nucleotide react at the mercury electrode essentially like the bases36 37 but adsorb more strongly than cytosine at a potential more positive than —1.6 V 37,48). The EI/2 for the reduction wave in the cytosine series becomes more positive in the order base > nucleotide > nucleoside, and is linearly pH-dependent 37,53). The mechanism for electrochemical reduction of cytosine, cytidine, CMP and CpC have been considered in terms of their structure, association in solution and adsorption 37). It was concluded that the deamination step for CpC occurs very slowly or not at all 37). 

Cytidine undergoes a one-step reduction in the pH range 2-7 l,37) with formation of an irreversible kinetic-diffusion wave 37). Coulometric determinations point to a 3-electron wave at pH 4.5 and a 4-electron wave at pH 7, , 84). 

In acid medium (pH 4.5) electrochemical reduction led to formation of two products. One of these was characterized as the 6,6 -dimer of the riboside of pyrimidone-2. It was photochemically converted to the riboside of pyrimidone-2. The second, on the basis of its chromatographic behaviour, UV spectrum, and reaction with the Fink reagent, was identified as the riboside of 3,6-dihydropyrimidone-2. The mechanism of electrochemical reduction of cytidine in acid medium is consequently analogous to that for 1-methylcytosine. The products of reduction of cytidine at pH 7 were shown chromatographically to contain 5,6-dihydrocytidine 1 84). A comparison of the electrochemical and catalytic reduction products under analogous conditions at pH 7 demonstrated that both led to the same products, one of them 5,6-dihydrocytidine 84). 

The foregoing proposed mechanism of reduction of cytosine, cytidine and their derivatives in acid and moderately alkaline media are further supported by the results of a recent study, by means of a.c. polarography, of the orientation of cytosine and cytidine at the mercury electrode. It was shown87) that, whereas at acid pH (about 5) both of these are adsorbed via the positive charge on the ring N3, so that the N3 = C4 bond is adjacent to the electrode surface, the orientation in alkaline medium (pH 9) is modified so that the C5 = C6 bond is located at the surface. This is consistent with the proposed mechanisms of reduction. 

Synthetic cytidine ribitol pyrophosphate was prepared by condensing cytidine 5-phosphate and D-ribose 5-phosphate in the presence of dicyclohexylcarbodiimide, followed by the reduction of the cytidine D-ribose pyrophosphate with sodium borohydride. 

Lawrence, C. C., Bennati, M., Obias, H. V., Bar, G., Griffin, R. G., and Stubbe, J., 1999, High-field EPR detection of a disulfide radical anion in the reduction of cytidine 5 -diphosphate by the E441Q R1 mutant of Escherichia coli ribonucleotide reductase. Proc. Natl. Acad. Sci. USA 96 8979ii8984. 

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