Pyrimidine nucleosides 3,4-dihydro— from

Numerous syntheses have also been reported for arabinofuranosyl nucleoside analogues, prepared either conventionally from arabinofuranosyl derivatives or via 2,2-anhydro-nucleosides obtained from appropriate ribonucleosides. 5-Aza-cytosine-D-arabinoside has been synthesized and found to show similar antiviral activity to Ara-C(arabinosyl-cytosine). 7-a-, 7-<3-, 9-0 -, and 9- 3-arabino-furanosyl derivatives of 3-deazaguanine have also been prepared, but none showed any anti-tumour activity. 9-(o -D-Arabinofuranosyl)-8-aza[2- C]-adenine, 7-(/3-D-arabinofuranosyl)-pyrrolo[2,3-d]pyrimidine-4(3//)-one (15)," l-(a-D-arabinofuranosyl)- and l-(/3-D-xylofuranosyl)-4-nitropyrazole, and Ot-arabino-nucleosides of 5-fluoro-cytosine and -uracil derivatives have also been prepared. An improved synthesis of 9-(/3-D-arabinofuranosyl)-2-fluoro-adenine has been reported. The ratio of o to 3 anomers obtained by phase-transfer reaction of 2,3,5-tri-O-benzyl-D-arabinofuranosyl bromide with 6-chloro-2-thiomethyl-7-deazapurine varied with the quaternary ammonium salt used as a catalyst, although the jU-anomer predominated in every case. 2,2-Anhydro-nucleosides have been used to prepare l-j3-D-arabinofiiranosyl derivatives of 5-alkylthio-uracils, 5-ethyl-cytosine, and 5-ethyl-uracil, 8-alkylamino-purines, and 2-aralkylamino-l,4-dihydro-4-imino-pyrimidine hydrochlorides (16). ... 

The Biosynthesis of the Pyrimidine Ring begins with aspartic acid and carbamyl phosphate. The latter is an energy-rich compound which reacts with the former to give carbamylaspartic acid. Ring closure consumes ATP and is in principle an acid amide formation (peptide synthesis). The intermediate dihydro-orotic acid is dehydrogenated to orotic acid, probably by action of a flavoprotein. Orotic acid is the key precursor of pyrimidine nucleotides. It reacts with phosphoribosyl pyrophosphate. The removal of pyrophosphate yields the nucleotide of orotic acid, whose enzymic decarboxylation produces uridine 5 -phosphate. Phosphorylation with ATP yields uridine pyrophosphate and, finally, uridine triphosphate. Beside the above pathway, there is the further possibility of converting free uracil and ribose 1-phosphate to the nucleoside and from there with ATP to the nucleotide. 

Other degradation products of the cytosine moiety were isolated and characterized. These include 5-hydroxy-2 -deoxycytidine (5-OHdCyd) (22) and 5-hydroxy-2 -deoxyuridine (5-OHdUrd) (23) that are produced from dehydration reactions of 5,6-dihydroxy-5,6-dihydro-2 -deoxycytidine (20) and 5,6-dihydroxy-5,6-dihydro-2 -deoxyuridine (21), respectively. MQ-photosen-sitized oxidation of dCyd also results in the formation of six minor nucleoside photoproducts, which include the two trans diastereomers of AT-(2-de-oxy-/j-D-eryf/iro-pentofuranosyl)-l-carbamoyl-4 5-dihydroxy-imidazolidin-2-one, h/1-(2-deoxy-J8-D-crythro-pentofuranosyl)-N4-ureidocarboxylic acid and the a and [5 anomers of N-(2-deoxy-D-eryfhro-pentosyl)-biuret [32, 53]. In contrast, formation of the latter compounds predominates in OH radical-mediated oxidation of the pyrimidine ring of dCyd, which involves preferential addition of OH radicals at C-5 followed by intramolecular cyclization of 6-hydroperoxy-5-hydroxy-5,6-dihydro-2 -deoxycytidine and subsequent generation of the 4,6-endoperoxides [53]. 

The 6-yl radicals produced by (the selective) [23, 24] addition of OH to C(5) of the C(5)/(6) double bond of naturally occurring pyrimidine bases, nucleosides and nucleotides or those formed by H-abstraction from C(6) of 5,6-dihydro-pyrimidines [25] react with para-substituted nitrobenzenes by addition (k 6xl0 to 2 X s ) to yield nitroxyl-type radicals which were... 

A two-step synthesis of modified 2 -C-nucleoside precursor, ethyl [2-(5-methyl-2,4-dioxo-3,4-dihydro-2i/-pyrimidin-l-yl)-4-hydroxyl-5-hydroxymethyltetra-hydrofuran-3-yl]fluoro-acetate 172, from protected glycal 170 and xanthate has been developed following the same idea, and a diastereomeric 1 1 mixture of 2,3-trans product 171 was obtained in 57% yield (O Scheme 46). The use of triethylborane as a free-radical initiator was less successful and a longer reaction time was also required. Interestingly, introducing th)miine at C-1 in the presence of silver triflate at 0°C was highly stereoselective, and only a C, C2-trans linked product was detected. 

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