Cytidine analogs

Azacitidine, a cytidine analog, causes hypomethylation of DNA, which normalizes the function of genes that control cell differentiation to promote normal cell maturation. The suspension is administered as a subcutaneous injection daily for 7 days for the treatment of myelodysplastic syndrome, a preleukemia disease. The pharmacokinetics of azacitidine are best described by a two-compartment model, with a terminal half life of 3.4 to 6.2 hours, whereas peak concentrations are achieved 30 minutes after a subcutaneous injection.7 Azacitidine has been shown to be clinically active in the treatment of myelodysplastic syndromes. The side effects include myelosuppression, renal tubular acidosis, renal dysfunction, and injection-site reactions. 

F. Garofolo, H. Pang, M. McIntosh, E. Wong, M. Kennedy, and A. Marland, Quantitation of a cytidine analog and its deaminated metabolite in animal and human plasma by LC-MS/MS, Proceedings of the 49th ASMS Conference on Mass Spectrometry,... 

Figure 4 Catalytic activation of cytosine for C5-methylation by nucleophilic addition of a thiolate at the C6 position, (a) The chemical mechanism of enzymatic DNA cytosine-S methylation. Mechanism-based inhibition of DMA MTases by cytidine analogs 5-fluoro-2 -deoxycytidine (b), 5-aza-2 -deoxy-cytidine (c), and 2-pyrimidinone-l-p-D-(2 -deoxyriboside) (d).

Gowher, H, Jeltsch, A. Mechanism of inhibition of DNA methyltransferases by cytidine analogs in cancer therapy. Cancer Biol. Ther. 2004 3 1062-1068. 

Nonaka, T., Nakamura, K. T., Uesugi, S., et al. (1993) Crystal structure of ribonuclease Ms (as a ribonuclease T1 homolog) complexed with a guanylyl-3, 5 -cytidine analog. Biochemistry, 32, 11825-11837. 

The pyridazine nucleosides, related to the naturally occurring nucleosides cytidine and uridine, have been prepared from 4,5-dichloropyridazin-6-one. Its trimethylsilyl derivative (106), when condensed with the protected ) -d-ribofuranose, affords the ) -nucleoside 107. From this the cytidine analog is obtained after treatment with ammonia and deprotection or, via the methoxy... 

The earliest mechanistic studies utilizing alternate substrates were first reported in 1976 by Thelander and co-workers on the inactivation of RDPR by 2 -chloro-2 -deoxyuridine 5 -diphosphate (CIUDP) and the cytidine analog, CICDP (9). 

Methylation occurs after replication and unmethylated sites in parental DNA remain unmethylated in daughter DNA. 5-Azacytidine, a cytidine analog that is metabolized like cytidine to the analog of dCTP (but cannot be methylated), can be incorporated into DNA. After replication replaces the modified C with a real C, it too remains unmethylated (see Figure 25.3b). 

The novel nitroxide spin label 15 (Fig. 1) was covalently incorporated into DNA by Sigurdsson and coworkers [33], It was integrated into the polycyclic fused ring system of a cytidine analog that forms a base pair with guanine. Therefore, the spin label cannot rotate around the intercoimecting bonds leading to very precise distance determination without spin label rotamers. Moreover, the relative orientation of the two nitroxide spin labels with respect to the distance vector can be extracted from the PELDOR time traces taken with variable observer frequency because the out-of-plane axis of the nitroxide is fixed with respect to the DNA molecule (Fig. 14) [113]. 

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