Ribonucleoside derivatives, reduction

Kawashima E, Aoyama Y, Sekine T, et al. Sonochemical and triethylborane-induced tin deuteride reduction for the highly diastereoselective synthesis of (2 R)-2 -deoxy [2 - H]ribonucleoside derivatives. J Org Chem. 1995 60 6980-6986. 

Pyrimidine ribonucleotides, like those of purines, may be synthesized de novo from amino acids and other small molecules (Chapter 11). Preformed pyrimidine bases and their ribonucleoside derivatives, derived from the diet of animals or found in the environment of cells, may be converted to ribonucleotides via nucleoside phosphorylases and nucleoside kinases. In some cells a more direct pyrimidine phosphoribosyltransferase pathway has also been recognized (Chapter 12). Ribonucleotides are catabolized by dephosphorylation, deamination, and cleavage of the glycosidic bond, to uracil. Uracil may be either oxidatively or reductively cleaved, depending on the organism involved, and can be converted to CO and NH (Chapter 13). 

When cytidine was the sole pyrimidine source (Table 14r-II), polynucleotide cytidylate and deoxycytidylate had identical specific activities and were incorporated without dilution. This is convincing evidence that in E. colt, reduction of ribonucleoside derivatives is able to supply all of the deoxyribose for DNA components without appreciable contribution from other sources, such as the postulated sequence involving deoxyri-boaldolase mentioned above. It will be recognized that this result does not preclude the possibility that alternate routes of deoxyribosyl biosynthesis may operate in circumstances other than the special ones of the Karlstrdm and Larsson experiment. The details of ribonucleotide reduction are discussed at length in Chapter 16. 

The concept that the deoxyribosyl groups of DNA nucleotides are derived by reduction of ribonucleoside derivatives is based on a wide array of experimental evidence. 

The synthesis of DNA is dependent on a ready supply of deoxyribonucleotides. The substrates for these are the ribonucleoside diphosphates ADP, GDP, CDP, and UDP the enzyme responsible for the reduction of these substrates to their corresponding deoxy derivatives is ribonucleotide reductase, which has thioredoxin as a cosubstrate. 

At the present time, it is rather difficult to evaluate the various conflicting interpretations of the available data. Perhaps the simplest view of the pentose phosphate pathway is that the oxidative branch functions to provide NADPH, a source of hydrogen for reductive biosyntheses, and to provide pentose phosphates the nonoxidative branch functions to reutilize pentose phosphates, which may be derived from ribonucleoside degradation, or are synthesized oxidatively in excess of those required for nucleotide synthesis it may also provide pentose phosphates. Further studies are required to settle the many questions that still remain. 

The deoxyribonucleotides are derived primarily, if not entirely, by reduction of ribonucleoside phosphates each of the several known ribonucleotide reductases (see Chapter 16) accepts as substrates phosphate esters of all four ribonucleosides, adenosine, guanosine, cytidine, and uridine. The ultimate fate of the uracil-containing reduction product, dUDP (or dUTP, in some microorganisms) is conversion to thymidine phosphates by way of deoxyuridylate and the thymidylate s mthetase reaction. 

The synthetic approach to 4 -(hydroxymethyl)ribonucleosides shown in Scheme 88 is based on aldol coupling of the nucleoside-5 -aldehyde (583) with formaldehyde and accompanying Cannizzaro reduction by the excess of formaldehyde. The 2, 3 -0-methylene derivative (584) was obtained as a by-product of the reaction. The branched-chain derivative (363) (see Chapter 13) also condensed with a variety of heterocyclic derivatives e.g. 6-chloropurine and JV -benzoyl-N ,9-bis(trimethylsilyl)adenine] to give, after deacetylation, 4 -(hydroxymethyl)ribo-nucleosides. -6-Chloro-9-(5,5-dimethylfuran-2-yl)purine (585) has been synthesized using the triol (586) derived from L-glutamic acid (see Scheme 65). ... 

Earlier data and those derived from these inhibition studies can be summarized in a model of ribonucleoside diphosphate reductase in which the active site is formed both from B1 and B2. It contains active dithiols contributed by Bl and a free radical contributed by B2. The active dithiols donate the electrons required for ribonucleotide reduction while participating in catalysis the function and nature of the free radical remain unknown. 

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