D-Thymidine

The base sequence and the tertiary structure of the yeast tRNA specific for phenylalanine (tRNA " ) is typical of all tRNAs. The molecule (see also p.86) contains a high proportion of unusual and modified components (shaded in dark green in Fig. 1). These include pseudouridine (T), dihydrouridine (D), thymidine (T), which otherwise only occurs in DNA, and many methylated nucleotides such as 7-methylguanidine (m G) and—in the anticodon—2 -0-methylguanidine (m G). Numerous base pairs, sometimes deviating from the usual pattern, stabilize the molecule s conformation (2). 

Prasad, A. S., Oberleas, D., Thymidine Kinase Activity and Incorpora-... 

The desired glycan derivative 66 was accessed by performing a nucleobase elimination on the TlPS-protected D-thymidine. " The synthesis ccmtinued with the formylation of 66 followed by reduction to give the primary alcohol 67. Conversion of the alcohol to the halide provided the iodide 64, which was coupled to pyrrole 40 (Scheme 23). ... 

Branch at C-4 - The syntheses of some C-4 branched derivatives of NeuNAc have been achieved from a protected 4-keto analogue, methyl (methyl 5-acetamido-3,5-dideoxy-8,9-6>-isopropylidene-p-D-manno-2,4-nonudiulopyrano-sid)onate. For example conversion of the latter into spiro-epoxide 12 by reaction with zirconocene dichloride-Zn-diiodomethane, then peracid, provided a reactive centre for the addition of carbon centred nucleophiles giving products such as 13. The synthesis of furo[2,3-c]pyran-P-D-thymidine, a potential antiviral agent, is mentioned in Chapter 20. 

Telbivudine (3), a synthetic thymidine nucleoside analog, is the unmodified L-enantiomer of the naturally occurring D-thymidine. It prevents HBV DNA synthesis by acting as an HBV polymerase inhibitor. Within hepatocytes, telbivudine (3) is phosphorylated by host cell kinase to telbivudine-5 -triphosphate which, once incorporated into HBV DNA, causes DNA chain termination, thus inhibiting HBV replication. In this sense, telbivudine (3), like most nucleotide antiviral drugs, is a prodrug. Clinical trials have shown telbivudine (3) to be significantly more effective than lamivudine (2) or adefovir dipivoxil (4) and less likely to cause resistance. ... 

A. Adenine series B. Guanine series C. Cytosine series D. Thymidine triphosphate. Chromatography of series C and D was performed after silica cartridge fractionation (see Methods and Materials)-... 

Competitive Inhibition of enzymes. In the case of competitive inhibition, the structural analogs compete with the natural substrates for the active site of enzymes. The enzymes of nucleic acid, and protein, synthesis can also be inhibited in this way. Thus, the enzyme thymidilate synthetase is competitively inhibited by 5-fiuorodeoxyuridine, a derivative of 5-fluorouracil (Fig. 14). Thymidilate synthetase supplies d-thymidine-5 -phosphate (-thymidilate), a substance which is important to the synthesis of DNA. Inhibition of this enzyme thus brings DNA synthesis to a stop and, with it, all further development. We will discuss DNA synthesis and also thymidilate synthetase in more detail later (p. 165). 

BVdU is degraded by thymidine phosphorylase more rapidly than the natural substrate, thymidine. This rapid enzymic degradation may present a problem in its clinical use. Moreover, herpes vimses develop resistance to BVdU, apparendy because of mutant vimses that have lower thymidine kinase activity. G. D. Seade has dropped further development of BVdU because of increased animal tumor incidence induced by prolonged dosing (1). 

Thymine was isolated from hydrolyzates of bovine thymus or spleen in 1893, several years before uracil, but it was not made synthetically until 1901. Unlike uracil, it comes not from ribonucleic but from deoxyribonucleic acids via thymidine (3-D-2 -deoxyribofuranosidothymine). 

Bei der Photoreduktion von Uridin wird als Nebenprodukt durch Photohydratation 6-Hydroxy-2,4-dioxo-I-(fi-D-ribofuranosyl)-hexahydro-pyrimidin gebildet. Die Photoreduktion von Thymidin mit Natriumboranat ver-lauft langsamer und kann nicht vom zweiten, Licht-unabhangigen Schritt abgegrenzt werden2. 

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 ),... 

Posttranslational modification of preformed polynucleotides can generate additional bases such as pseudouridine, in which D-ribose is linked to C-5 of uracil by a carbon-to-carbon bond rather than by a P-N-glycosidic bond. The nucleotide pseudouridylic acid T arises by rearrangement of UMP of a preformed tRNA. Similarly, methylation by S-adenosylmethionine of a UMP of preformed tRNA forms TMP (thymidine monophosphate), which contains ribose rather than de-oxyribose. 

The regions of the tRNA molecule teferred to in Chapter 35 (and illustrated in Figure 35-11) now become important. The thymidine-pseudouridine-cyti-dine (T PC) arm is involved in binding of the amino-acyl-tRNA to the ribosomal surface at the site of protein synthesis. The D arm is one of the sites important for the proper recognition of a given tRNA species by its proper aminoacyl-tRNA synthetase. The acceptor arm, located at the 3 -hydroxyl adenosyl terminal, is the site of attachment of the specific amino acid. 

Fig. 5.22 Thymidine (A), guanosine (B) and some nucleoside analogues (C-J). C, idoxuridine D, cytarabine E, ribavirin F, zidovudine (AZT) G, dideoxycytidine (DDC) H, dideoxyinosine (DDI) I, acyclovir J, ganciclovir.

Heig, M.E., Ulrich, D., Sagelsdorff, P., Richter, C. and Lutz, W.K. (1990). No measurable increase in thymidine glycol or 8-hydroxydeoxyguanosine in liver DNA of rats treated with nafenopin or choline-devoid low-methionine diet. Mut. Res. 238, 325-329. 

N3-coordination by monomeric and dimeric Zn2+-cyclen derivatives has also been shown to both inhibit the photo [2+2] cycloaddition of thymidilyl(3 -5 )thymidine, d(TpT), and to accelerate the photosplitting process of the [T-cis,syn-T] dimer (78% after 1 h of UV exposure) (38). 

Huang P, Farquhar D, Plunkett W. Selective action of 3 -azido-3 -deoxy-thymidine 5 -triphosphate on viral reverse transcriptases and human DNA polymerases. J Biol Chem 1990 265 11914-11918. 

Gustavsson T, Sharonov A, Markovitsi D (2002) Thymine, thymidine and thymidine 5 -monophosphate studied by femtosecond fluorescence upconversion spectroscopy. Chem Phys Lett 351 195... 

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