Pyrimidine nucleotides analogues

The Lewis acid-mediated A -glycosylation of 2,3-dideoxyribofuranosides having a (diethoxyphosphorothioyl)difluoromethyl group at the 3a-position with silylated nucleobases has been reported to be successful for the diastereo-selective synthesis of (3-A -pyrimidine-nucleotide analogues, (56-59). ... 

Cidofovir is a synthetic acyclic pyrimidine nucleotide analogue of cytosine (42). It is a phosphorylated nucleotide that is additionally phosphorylated by host cell enzymes to its active intracellular metabolite, cidofovir diphosphate. This reaction occurs without initial virus-dependent phosphorylation by viral nucleoside kinases. It has antiviral effects by interfering with DNA synthesis and inhibiting viral replication. 

Azacytidine (SED VIII, p. 961) is a pyrimidine nucleotide analogue. It is probably a cell cycle specific agent but also has an effect on resting cells. It has been found of little value in the treatment of solid tumours but has been of interest as a possible remission-inducing agent in acute non-lymphoblastic leukaemia. 

The acyclic nucleoside phosphonates (ANPs) can be considered as nucleotide rather than nucleoside analogues, in that, besides the purine or pyrimidine base, they contain an (acyclic) sugar moiety to which a phosphonate is attached. In these nucleotide analogues (Fig. 2), the phosphoric ester grouping (= P-O---C-----) is... 

Not all analogues become active against cancer cells through incorporation into nucleic acid. Some analogues block the synthesis of normal purine and pyrimidine nucleotides for example, 8-azaguanine blocks guanosine monophosphate (GMP) synthesis and 6-mercaptopurine inhibits adenosine monophosphate (AMP) syn-thesis. 

NMR investigations of some carbohydrate-substituted tetrazolo[l,5-h]pyrimidin-5(6//)ones as nucleotide analogues have been studied by Chu et al. <1997JOC7267>. The H and 13C chemical shifts of these derivatives are shown in Table 3. 

The pyrimidine antagonists inhibit the biosynthesis of pyrimidine nucleotides or interfere with vital cellular functions, such as the synthesis or function of nucleic acids. The analogues of deoxycytidine and thymidine that are used are inhibitors of DNA synthesis while 5-fluorouracil (5-FU) an analogue of uracil, is an inhibitor of both RNA function and of the synthesis of thymidylate (see Fig. 2). PALA (N-phosphonoacetyl-L-aspartate), an inhibitor of as-... 

The first marketed NRTI for HIV was zidovidine (Retrovir, 6.10) (Figure 6.19). Zidovidine is a pyrimidine nucleoside analogue. Substitution of the 3 -hydroxyl with an azido group makes chain elongation of the DNA strand impossible upon zidovidine incorporation. Although nucleotides are the required substrate of RT, most NRTIs are nucleo. Vfe.s. Zidovidine and other NRTIs are transported into a cell without any 5 -phosphates. Once in a cell, the... 

C20 Chelbova, K. V., Golovinsky, E. V. and Hadjiolov, A. A. The action of some orotic acid analogues on the in vitro incorporation of [i C]-orotate into pyrimidine nucleotides. Biochem. Pharmacol., 19, 2785-2789 (1970)... 

Figure 14 Chemical structures of l,N -ethenoadenosine 5 -monophosphate (8-AMP ) and of uridine 5 -0-thiomonophosphate (UMPS ), as well as of the dianion of the acyclic nucleotide analogue 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA ). To facilitate comparisons between e-AMP and AMP the conventional atom numbering for adenines is adapted, a procedure which is common [171]. The purine-nucleotide e-AMP [11-13] and the pyrimidine-nucleotide UMPS [11,14] are shown in their dominating anti conformation. H-NMR shift measurements have shown [176] that in solution PMEA adopts an orientation which is similar to the anti conformation of AMP this conclusion is in accord with a crystal structure study [177] of the H2(PMEA) zwitterion.

Brel reported an efficient synthesis of a series of new purine and pyrimidine nucleotides containing acyclic phosphonate analogues with a triple or double bond (54) in the carbon skeleton. 

Potentially tautomeric pyrimidines and purines are /V-alkylated under two-phase conditions, using tetra-n-butylammonium bromide or Aliquat as the catalyst [75-77], Alkylation of, for example, uracil, thiamine, and cytosine yield the 1-mono-and 1,3-dialkylated derivatives [77-81]. Theobromine and other xanthines are alkylated at N1 and/or at N3, but adenine is preferentially alkylated at N9 (70-80%), with smaller amounts of the N3-alkylated derivative (20-25%), under the basic two-phase conditions [76]. These observations should be compared with the preferential alkylation at N3 under neutral conditions. The procedure is of importance in the derivatization of nucleic acids and it has been developed for the /V-alkylation of nucleosides and nucleotides using haloalkanes or trialkyl phosphates in the presence of tetra-n-butylammonium fluoride [80], Under analogous conditions, pyrimidine nucleosides are O-acylated [79]. The catalysed alkylation reactions have been extended to the glycosidation of pyrrolo[2,3-r/]pyrimidines, pyrrolo[3,2-c]pyridines, and pyrazolo[3,4-r/]pyrimidines (e.g. Scheme 5.20) [e.g. 82-88] as a route to potentially biologically active azapurine analogues. 

Since one of the catalytic actions of reverse transcriptase is DNA synthesis, analogues of pyrimidine and purine nucleotides inhibit this process. A drug, zidovudine, azi-... 

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