Thymidine , preparation

Deoxy-5 -iodo-2, 3 -0-isopropylidene-thymidine, prepared conventionally from thymidine, has been used to prepare the 5 -modified nucleosides illustrated in Scheme 1. ... 

Copper(I) tends towards a tetrahedral coordination geometry in complexes. With 2,2 -bipyr-idine as a chelate ligand a distorted tetrahedral coordination with almost orthogonal ligands results. 2,2 -Bipyridine oligomers with flexible 6,6 -links therefore form double helices with two 2,2 -bipyridine units per copper(I) ion (J. M. Lehn, 1987,1988). J. M. Lehn (1990 U. Koert, 1990) has also prepared such helicates with nucleosides, e.g., thymidine, covalently attached to suitable spacers to obtain water-soluble double helix complexes, so-called inverted DNA , with internal positive charges and external nucleic bases. Cooperative effects lead preferentially to two identical strands in these helicates when copper(I) ions are added to a mixture of two different homooligomers. 

Trifluridine, C2qH22F2N20, (5-trifluoromethyl-2 -deoxyuridine [70-00-8] F TdU, 14) was first prepared (30) in 1962. It is used for topical therapy of herpes vims-infected eyes. It is especially usefiil for treating infections that are resistant to IdU therapy. Like IdU, trifluridine is incorporated into DNA in place of thymidine in both infected and uninfected cells. But it is 10 times more potent than IdU against herpes keratitis in rabbits and 10 times more soluble in water. Trifluridine is also usefiil in treating human cytomegalovims (HCMV), but its toxicity to bone marrow may limit its clinical use. 

An isobutyl carbonate was prepared by reaction with isobutyl chloroformate (Pyr, 20°, 3 days, 73% yield), to protect the 5 -OH group in thymidine. It was cleaved by acidic hydrolysis (80% AcOH, reflux, 15 min, 88% yield). ... 

An amount of enzyme preparation equivalent to 900 mg of wet cells was made up to 25 ml with the above potassium phosphate buffer solution. 150 mg (1.15 mmol) of 5-fluorouracil and 1.0 gram of thymidine (4.12 mmol) were dissolved in 15 ml of the above potassium phosphate buffer solution. The mixture was incubated at 37°C for 18 hours. After this time, enzyme action was stopped by the addition of four volumes of acetone and one volume of peroxide-free diethyl ether. The precipitated solids were removed by filtration, and the filtrate was evaporated under nitrogen at reduced pressure until substantially all volatile organic solvent had been removed. About 20 ml of aqueous solution, essentially free of organic solvent, remained. This solution was diluted to 100 ml with distilled water. 

Deoxy-3 -fluorothymidine (813), a selective inhibitor of DNA synthesis, was prepared " in moderate yields from 3 -0-mesyl- or 3, 5 -di-O-mesyl-thymidine, through 2,3 -anhydro-1 -(2-deoxy- -D-t/2reopentofur-anosyl)thymine (808), by treatment with hydrogen fluoride (0.1% HF in l,4-dioxane-AlF3, 3.764 hf in DMF-AlFj, or 10% HF in DMF ),... 

Deoxy-5 -fluorothymidine (838) was prepared by Langen and Kowol-jj. 796,797 fpQjyj 5 -0-tosyl precursor by treatment with fluoride. Compound 838 cannot be phosphorylated enzymically owing to the lack of OH-5, but it inhibits the growth of carcinoma cells. This was explained as follows the thymidine 5 -monophosphate (thymidylate) kinase in carcinoma cells, catalyzing the transformation of thymidine 5 -monophosphate into the diphosphate, is inhibited by 838, thus preventing the synthesis of... 

The animation of thymidine derivatives can also be carried out as a one-pot reaction, in which the ditetrazolide is prepared in situ from the corresponding dichloride and tetrazole.[1963 Similar reactions are described in references [197], [198] and [33a]. 

Incorporation of a flavin electron donor and a thymine dimer acceptor into DNA double strands was achieved as depicted in Scheme 5 using a complex phosphoramidite/H-phosphonate/phosphoramidite DNA synthesis protocol. For the preparation of a flavin-base, which fits well into a DNA double strand structure, riboflavin was reacted with benzaldehyde-dimethylacetale to rigidify the ribityl-chain as a part of a 1,3-dioxane substructure [49]. The benzacetal-protected flavin was finally converted into the 5 -dimethoxytri-tyl-protected-3 -H-phosphonate ready for the incorporation into DNA using machine assisted DNA synthesis (Scheme 5a). For the cyclobutane pyrimidine dimer acceptor, a formacetal-linked thymine dimer phosphoramidite was prepared, which was found to be accessible in large quantities [50]. Both the flavin base and the formacetal-linked thymidine dimer, were finally incorporated into DNA strands like 7-12 (Scheme 5c). As depicted in... 

A somewhat related microwave-promoted 5 -0-allylation of thymidine has been described by the Zerrouki group (Scheme 6.108) [215], While the classical method for the preparation of 5 -0-allylthymidine required various protection steps (four synthetic steps in total), the authors attempted the direct allylation of thymidine under basic conditions. Employing sodium hydride as a base at room temperature in N,N-dimethylformamide resulted in the formation of per-allylated compounds along with the desired monoallylated product (75% yield). The best result was achieved when both the deprotonation with sodium hydride (1.15 equivalents) and the subsequent allylation (1.2 equivalents of allyl bromide) were conducted under... 

The readily prepared immobilized phosphoramidite could be used to efficiently synthesize oligodeoxyribonucleotides with modified thymidine residues. Whereas the effect of microwave irradiation on the deprotection by exposing the strand to tet-rakis-triphenylphosphine palladium(O) and diethylammonium bicarbonate was only small using dichloromethane as solvent, complete removal of the alloc group was achieved in N,N-dimethylformamide within 10 min at 80 °C (Scheme 7.30). After the reaction, the solid-supported product was washed with N,N-dimethylformamide and dichloromethane and dried, before being subjected to acylation. The coupling... 

Tipson devoted most of his years in Levene s laboratory accomplishing seminal work on the components of nucleic acids. To determine the ring forms of the ribose component of the ribonucleosides he applied Haworth s methylation technique and established the furanoid structure for the sugar in adenosine, guanosine, uridine, and thymidine. He showed that formation of a monotrityl ether is not a reliable proof for the presence of a primary alcohol group in a nucleoside, whereas a tosyl ester that is readily displaced by iodide affords clear evidence that the ester is at the 5-position of the pentofuranose. Acetonation of ribonucleosides was shown to give the 2, 3 -C -isopropyl-idene derivatives, which were to become extensively used in nucleoside and nucleotide chemistry, and were utilized by Tipson in the first chemical preparation of a ribonucleotide, inosinic acid. 

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