Thymidine dimers

Upon absorption of UV radiation from sunlight the bases can proceed through photochemical reactions that can lead to photodamage in the nucleic acids. Photochemical reactions do occur in the bases, with thymidine dimerization being a primary result, but at low rates. The bases are quite stable to photochemical damage, having efficient ways to dissipate the harmful electronic energy, as indicated by their ultrashort excited state lifetimes. It had been known for years that the excited states were short lived, and that fluorescence quantum yields are very low for all bases [4, 81, 82], Femtosecond laser spectroscopy has, in recent years, enabled a much... 

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... 

Van Gelder That is the photolyase model. In photolyase, the damaged DNA is bound in the dark, and then dissociates following the light-mediated enzymatic repair of the thymidine dimer. Photolyases are believed to be the molecular ancestors of cryptochromes. 

As already indicated, the repair processes may inadvertently contribute to errors leading to mutation and more serious endpoints. Some chemicals can affect the repair process, so increasing mutation rates. Lack of a repair system also leads to increased mutations and cancer as occurs in patients suffering from the disease xerodermum pigentosum. These individuals are unable to remove thymidine dimers formed by exposure to ultraviolet light in the DNA of skin cells. They consequently suffer a very high incidence of skin cancer. 

Ultraviolet light causes photodimerization of adjacent pyrimidine residues in DNA, such as the formation of thymidine-thymidine dimers. 

Thymidine dimers in which the natural phosphodiester linkage has been replaced by a 2,5-disubstituted tetrazole ring have been synthesized and have been incorporated into oligodeoxynucleotides <02HCA2847>. The synthesis of mono- and bis-3-substituted thymidine derivatives with a polycyclic tetrazole linker (l,5-bis(tetrazol-5-yl)-3-oxapentane) has been reported <02TL1901>. a-Methylene tetrazole-based peptidomimetics were synthesized for inhibition studies of HIV protease <02JCS(P1)172>. A catalytic amount of tetrazole was found to be useful in the syntheses of symmetrical P,P -dialkyl partial esters of methylenebisphosphonic acid from the corresponding acid chloride via a facile two-step, one-... 

The effect of introducing a sulfamate or sulfamide internucleotide linkage has been examined using the thymidine dimers (22). When incorporated into du-... 

Schwarz M, Pfleiderer W. Solution synthesis of fully protected thymidine dimers using various phosphoramidites. Tetrahedron Lett 24 5513-5516, 1984. 

A stereoselective synthesis of a thymidine dimer containing a non-anionic 3 -CH. -NH-0-... 

In a study of the synthesis of thymidine-3-phosphoramidites of various amines and their use in the synthesis of fully protected thymidine dimers, a series of monoazacycloalkanes was tested as the amine component <84TL5513>. It was shown that the condensations in solution work especially well with yields exceeding 90% when p-nitrophenylethyl phosphoramidites of hexahydroazepine, octahydroazonine, and azacyclotridecane were used. These compounds can easily be purified and stored at room temperature, so that they might be useful synthons for large-scale synthesis of oligodeoxyribonucleotides, where a low excess of phosphoramidites is desirable. 

SCHEME 2.8 Synthesis of a CBMP-modified thymidine dimer 50. (Adapted from Lesnikowski, Z. J. Schinazi, R. F. 1993. J. Org. Chem. 58 6531-6534.)... 

An efficient synthesis of the bis(phosphonate) 153 has been described, and a route to a thymidine dimer containing an intemucleoside phosphinite link is outlined in Scheme 10, the dimeric unit being incorporated into oligodeoxynu-cleotides. The dinucleotide 154 with a novel hydroxymethylphosphonate link was prepared by reaction of a dithymidinyl trimethylsilylphosphite with formaldehyde the procedure could be carried out on a solid support to give a decathymidylate with all links modified. Also reported is a procedure for the... 

The all-carbon alkene replacement 169 has been prepared by a Wittig reaction, and could be isomerized to the rra/u-alkene. Both analogues were incorporated into oligodeoxynucleotides and compared with the amide replacements (Tm values). The trons-alkene was expected to have the higher Tm, but it was not in fact much higher than for the cw-isomer. The 5-atom replacements 170 and 172 have been made and incorporated into decamers for comparison with the previously-reported 4-atom types 171 and 173 it was found that the 4-atom link gave more stable complexes for the amides, but the reverse was the case for the secondary amines. There has been further work reported on the CH2NHCH2CH2 replacement, and thymidine dimers 174 with a chiral centre in the link have been described (both diastereomers). ... 

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