Thymidine analogues

Stavudine is an other thymidine analogue with a similar mechanism of action and activity as zidovudine. It can be used in AIDS patients who responded insufficiently to zidovudine or who cannot tolerate zidovudine. Its most prominent dose dependent toxicity is d4T induced neuropathy. 

It is a thymidine analogue. After phosphorylation in body zidovudine triphosphate selectively inhibits viral reverse transcriptase i.e. RNA dependent DNA polymerase. It is effective against retrovirus only. 

All NRTIs may be associated with mitochondrial toxicity, probably owing to inhibition of mitochondrial DNA polymerase gamma. Less commonly, lactic acidosis with hepatic steatosis may occur, which can be fatal. NRTI treatment should be suspended in the setting of rapidly rising aminotransferase levels, progressive hepatomegaly, or metabolic acidosis of unknown cause. The thymidine analogues zidovudine and stavudine may be particularly associated with dyslipidemia and insulin resistance. Also,... 

THYMIDINE KINASE (TK) An enzyme involved in the utilization of the nucleoside thymidine (which ultimately becomes part of the structure of DNA) catalyzes the phosphorylation of thymidine to thymidine monophosphate mutants that lack TK are resistant to the toxic effects of several thymidine analogues, including bromodeoxy-uridine and trifluorothymidine selection of these drug-resistant mutants provides the basis of several... 

Thirty 5 -thiourea-substituted a-thymidine analogues used to develop receptor-independent 4D-QSARmodels ( 3 = 0.83) for thymidine monophosphate kinase inhibitors. The model was also put into the context of reported crystallographically characterized inhibitor/enzyme interactions... 

Andrade CH, Pasqualoto KF, Ferreira El, Hopfinger AJ (2009) Rational design and 3D-pharmacophore mapping of 5 -thiourea-substituted alpha-thymidine analogues as mycobacterial TMPK inhibitors. J Chem Inf Model 49 1070-1078... 

Conventional chemistry converted carbinol 277 into acyl azide 278, which was treated under Curtius rearrangement conditions to obtain either amine 279 or urea derivative 280, the respective precursors of guanine derivative 281 and thymidine analogue 282. 

Alternatively, isoxazolidin-5-yl acetates were obtained by reduction and acetylation of suitable isoxazolidin-5-ones, which, in turn, were prepared by diastereoselective Michael addition of hydroxylamines to unsaturated esters or by nucleophilic addition of enolates to nitrones and subsequent cyclization of the resulting hydroxylamines. For example, the two diastereomeric isoxazolidinones 552 were converted into thymidine analogues 590 (Scheme 146) <1997JOC7430, 1998T6587, 2000TL9239, 2005CRC775>. 

Benhida described the synthesis of a 2-deoxy-C-nucleoside analogue and its phosphoramidite derivative featuring 6-(thiazolyl-5)-a-benzimidazole nucleobase (134). A more efficient route to the expanded adenosine analogue (135) was developed by Kool, who also described the synthesis of the expanded thymidine analogue (136) starting from 5-methylanthranilic acid. Both nucleosides were found to be efficient fluorophores. 3 -Cyanoethyl phosphoramidites of 6-methyl-3-(2 -deoxy-(3-D-ribofuranosyl)-3//-pyrrolo[2,3-d]pyrimidin-2-one... 

The synthesis of pyrimidine 3 -phosphorothioamidites has been carried out to prepare ODNs containing 3 -5 -phosphorothiolate linkages for mechanistic studies.The stereospecific synthesis of 3 -deuterated pyrimidine nucleosides for NMR studies of ODNs has also been reported.The incorporation into DNA of a thymidine analogue bearing a 3 -methyl group was shown to be destabilising with both complementary DNA and RNA, though less so with RNA. ° ... 

Abramov nucleophilic addition of various phosphorus acid esters to nucleoside aldehyde derivatives yielded the phosphonate-based iso-polar, non-iso-steric 5 -nucleotide analogues (28) containing a geminal hydroxy phosphonate moiety on the 5 -carbon of the pentofuranose ring. The enantiomerically pure D- and l- 2, 3, 5 -trideoxy-4 -[(ethoxyphosphoryl) difluoromethyl] thymidine analogues(29) have been synthesized from (i 5)-( )-2-methyl-5-(4-methyl-phenyl-sulfinyl)pent-2-ene and ethyl 2-(diethoxyphosphoryl)-2,2-difluoro-acetate in 45% overall yield over seven steps. ... 

Administration of mitotic inhibitor and thymidine analogue shortly before tissue sampling might impact the... 

Fig. 5.9 Mode of action of radiolabeled thymidine analogues used for imaging cellular proliferation. The radiotracers are transported and phosphory-lated by thymidine kinase (salvage pathway) to the corresponding monophosphate that is subsequently phosphorylated to the triphosphate and...

B = thymidine). Analogues of the general structural types (456) and (457) were... 

Fig. 5.7. Activation, incorporation, and chain-terminating action of azidothymidine (AZT), a thymidine analogue, as a reversible inhibitor of human immunodeficiency virus-reverse transcriptase (HIV-RT).

---