Pyrimidine deoxyribonucleosides

Prusoff WH, Chen MS, Fischer PH, Lin TS, Shiau GT, Schinazi RF, Walker J (1979) Antiviral iodinated pyrimidine deoxyribonucleosides 5-iodo-2 -deoxyuridine 5-iodo-2 -deoxycytidine 5-iodo-5 -amino-2, 5 -dideoxyuridine, Pharmacol Ther 7 1-34... 

Wondrack LM, C-A Hsu, MT Abbott (1978) Thymine-7-hydroxylase and pyrimidine deoxyribonucleoside 2 -hydroxylase activities m Rhodotorula glutinis. J Biol Chem 253 6511-6515. 

Wetzstein H-G, N Schmeer, W Karl (1997) Degradation of the fluoroquinolone enrofloxacin by the brown-rot fungus Gleophyllum striatum identification of metabolites. Appl Environ Microbiol 63 4272-4281. Wondrack LM, C-A Hsu, MT Abbott (1978) Thymine-7-hydroxylase and pyrimidine deoxyribonucleoside 2 -hydroxylase activities in Rhodotorula glutinis. J Biol Chem 253 6511-6515. 

Thymidine, 2 oxoglutarate dioxygenase 1.14.11.3 (Pyrimidine deoxyribonucleoside 2 -hydroxylase... 

Evidence presented by W. C. Schneider [/. Biol. Chem., 216, 287 (1955)1 indicates that pyrimidine deoxyribonucleosides themselves are normally present within certain mammalian tissues. He suggests that these pyrimidine deoxyribonucleosides in tissues function principally in the synthesis of deoxyribonucleic acid. 

Thymidine, 2-oxoglutarate oxygen oxidoreductase (2 -hydroxylating), or Thymidine, 2-oxoglutarate dioxygenase, or Thymidine 2 -hydroxylase, or Pyrimidine deoxyribonucleoside 2 -hydroxylase (EC 1.14.11.3). It catalyses hydroxylation of C2 of the deoxyribose moiety of thymidine. 

Fig. 2-6. The torsion angle in a pyrimidine deoxyribonucleoside. The observer is looking from C-l to N-1.

This discussion will be concerned mainly with uracil, cytosine, and their ribonucleosides the metabolism of these compounds is summarized in Fig. 12-1. The metabolism of pyrimidine deoxyribonucleosides is considered in Chapter 14. Incorporation into the polynucleotides of uracil, cytosine, and their ribonucleosides proceeds by way of the ribonucleotide pool. 

Although cells derive their deoxyribonucleotides primarily by reduction of ribonucleotides, the deoxyribonucleosides can be utilized to some extent by way of kinase reactions. Phosphorylation of deoxyribonucleosides represents the only known point of entry into the sequences of deoxyribonucleotide metabolism other than the main entry point, ribonucleotide reduction. Pyrimidine deoxyribonucleosides may be incorporated into DNA in animal cells by this route. The conversion of deoxyadenosine and deoxyguanosine into deoxyribonucleotides and thence into DNA would also appear possible by a kinase-initiated sequence, because the enzymatic phosphorylation of these compounds has been demonstrated. However, this route has not been well studied in animal cells and its assessment is complicated by very active deamination and phosphorolytic cleavage reactions which compete with the reactions leading to DNA. E. coli cells appear to possess only one kinase capable of phosphorylating deoxyribonucleosides, thymidine kinase. 

Although uridine is the preferred substrate of the uridine phosphorylase of animal tissues, deoxyuridine and thymidine are also cleaved at appreciable rates. The uridine phosphorylase activity of dog tissues readily cleaves deoxyuridine and thymidine and, in fact, may be the only means by which the pyrimidine deoxyribonucleosides are phosphorolyzed in dog tissues, because thymidine phosphorylase is absent from a number of them (9) (see Chapter 12). Uridine phosphorylase of E. coli is highly specific toward the ribosyl portion of its substrate and cleavage of deoxyribonucleosides is slower relative to uridine than with the animal enzymes (5). 

The pathways by which purine and pyrimidine deoxyribonucleosides are metabolized are summarized below. The enzymes are listed in Table 14r III. 

Reaction sequences by which the pyrimidine deoxyribonucleosides and deoxyribonucleotides are interconverted are summarized below (steps... 

Procedure A solution of 50—500 (xg nucleic acid in 1 ml water is heated 10 min at 100° C with 2 ml of a solution of 1 g diphenylamine and 2.75 ml cone, sulphuric acid in 100 ml acetic acid. The solution turns blue (abs. max. 595 nm) if deoxyribonucleic acid is present. The difficultly hydrolysable pyrimidine-deoxyribonucleosides and -nucleotides do not react under these conditions. 

Table 1. Antiviral activity of various azido, amino, 2 ,3 -unsaturated, and 2, 3 -dideoxy analogues of pyrimidine deoxyribonucleosides on the replication of M-MuLV in 3T3 mouse cells. ...

Among the 3 -azido analogues of pyrimidine deoxyribonucleosides, 3 -azido-3 -deoxy-thymidine (2, AZT) was the most active against HIV-1 in vitro with an EC50 value of 0.002 jaM. Conversely, 3 -azido-3 -deoxy-6-azathymidine (37) was practically inactive (EC50 >100 aM). The 3 -azido derivatives of 3 -deoxy-3-(3-oxo-l-propenyl)thymidine (36), 2 -deoxyuridine (1), 5-bromo-2 -deoxyuridine (5), 2 -deoxy-5-fluorocytidine (8), 2 -deoxy-5-iodouridine (6), 2 -deoxycytidine (7), 2 -deoxy-5-fluorouridine (4), 2 -deoxy-5-thio-... 

Table 8. Comparison of the ECso values of several 3 -amino analogues of pyrimidine deoxyribonucleosides and their corresponding nitrosourea derivatives on the replication of L1210 cells in vitro.

K. E.B. Parkes, N.A. Roberts, G.J. Thomas, S.A. Galpin, and D. Kinchington, Synthesis and antiviral activity of monofluoro and difluoro analogues of pyrimidine deoxyribonucleosides against human immunodeficiency virus (HIV-1), 7. Med. Chem. 33 2137 (199.0). 

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