A-deoxycytidine

In summary, decitabine (1), a deoxycytidine derivative, is a potent antileukemic that is able to induce in vitro gene activation and cellular differentiation by a mechanism involving DNA hypomethylation. It is generally most beneficial in patients with high-risk MDS or in MDS patients with intermediate-2 or high-risk features. Its process synthesis and academic synthetic approaches have been summarized in this chapter. 

Nakatani-Freshwater, T., Babayeva, M., Dontabhaktuni, A., Taft, D. R. (2006). Effects of trimethoprim on the clearance of apricita-bine, a deoxycytidine analog reverse transcriptase inhibitor, and Lamivudine in the isolated perfused rat kidney. The Journal of Pharmacology and Experimental Therapeutics, 319, 941—947. 

Coleman, C.N. Stoller, R.G. Drake, J.C. Chabner, B.A. Deoxycytidine kinase properties of the enzyme from human leukemic granulocytes. Blood, 46, 791-803 (1975)... 

Self-anomerization reaction (3) with fully protected deoxycytidine lb is readily scaled up, and the corresponding a-anomer 2b is crystallized from toluene and then treated with 0.19M sodium hydroxide at 0°C for 5 min. After neutralization with Dowex 50W (pyridinium form), 4-A -benzoyl-a-deoxycytidine (2l2) is obtained as colorless crystals in 44% overall yield. 

Ara-A is phosphorylated in mammalian cells to ara-AMP by adenosine kinase and deoxycytidine kinase. Further phosphorylation to the di- and triphosphates, ara-ADP and ara-ATP, also occurs. In HSV-1 infected cells, ara-A also is converted to ara-ATP. Levels of ara-ATP correlate directly with HSV rephcation. It has recently been suggested that ara-A also may exhibit an antiviral effect against adenovims by inhibiting polyadenylation of viral messenger RNA (mRNA), which may then inhibit the proper transport of the viral mRNA from the cell nucleus. 

Write a structural formula for 2 -deoxycytidine 3 -monophos- phate. You may wish to refer to Table 28.2 for the structure of cytidine. J... 

Cladribine (2-Chlordeoxyadenosine) is a synthetic purine nucleoside that is converted to an active cytotoxic metabolite by the deoxycytidine kinase. The drug is relatively selective for both normal and malignant lymphoid cells. 

C2H3BrO 506-96-7) see Paclitaxel N-acetyl-2 -bromo-2 -deoxycytidine 3, S -diacetate (C 5HigBrN307 126430-12-4) see Zalcitabine A -acetyl-3 -bromo-3 -deoxycytidine 2, 5 -diacetate (C 5H gBrN307 126430-11-3) see Zalcitabine 2-acetyl-4-butyramidophenol (C 2H,5N03 40188-45-2) see Acebutolol... 

The cytotoxic activities of the 2, 2 -difluoro analog (775) of 737 against Chinese hamster ovary and tumor cells, in comparison with those of 1- -d-arabinofuranosylcytosine ara-C, a drug for leukemia), have been studied 775 is transported the faster through membrane into cells, more effectively phosphorylated by the deoxycytidine kinase (to the 5 -mono-phosphate) and, after conversion into the 5 -triphosphate, more highly accumulated in the cells, with longer duration time, than is ara-C, but nevertheless 775 is incorporated into the DNA to a lesser extent than is ara-C. These characteristics of 775 were discussed. 

C]-FlAC was synthesized from [2- C]cytosine in the general manner used for unlabeled 748 (FIAC), and its metabolic fate in mice was studied. The compound (after i.v. injection) was deaminated by cytosine nucleoside deaminase and appeared as [2- C]-FIAU in plasma, as confirmed by experiments on rats having a very low level of the deaminase, and by treatment with tetrahydrouridine, a nucleoside deaminase inhibitor. This was further confirmed by the use of purified human deoxycytidine deaminase. It was... 

The first etCCR application has been reported for a partially C— N-labeled phosphotyrosine peptide derived from interleukin-4 receptor ligated to STAT-6 [107] and subsequent studies involve nucleotide cofactors ligated to human recombinant deoxycytidine kinase [108] and epothilone A bound to tubulin [109]. Since etCCR usually involves isotope-labeling schemes for the ligand, its applicability is limited to specific molecular classes. 

Deamination, the hydrolytic loss of exocyclic amino groups on the DNA bases, is typically a very slow reaction. For example, deamination of cytosine residues in dnplex DNA occnrs with a half-life of about 30,000 years under physiological conditions, and the deamination of adenine residues is still more sluggish. " Alkylation at the N3-position of cytosine (Scheme 8.5) greatly increases the rate of deamination (ty2 = 406 h). Deamination of 3-methyl-2 -deoxycytidine proceeds 4000 times faster than the same reaction in the unalkylated nucleoside. Alkylation of the N3-position in cytosine residues also facilitates deglycosylation (Jy2 = 7700 h, lower pathway in Scheme 8.5), but the deamination reaction is 20 times faster and, therefore, predominates. ... 

For patients who do not respond to hydroxyurea, 5-azacytidine and 5-aza-2 -deoxycytidine (decitabine) may be useful. Both induce HbF by inhibiting methylation of DNA, preventing the switch from y- to (i-globulin production. Decitabine appears to be safer and more potent than 5-azacytadine. In a small study in adults refractory to hydroxyurea, decitabine 0.2 mg/kg subcutaneously one to three times weekly was associated with an increase in HbF in all patients. Additionally, RBC adhesion was reduced. Neutropenia was the only significant toxicity reported.6... 

Other degradation products of the cytosine moiety were isolated and characterized. These include 5-hydroxy-2 -deoxycytidine (5-OHdCyd) (22) and 5-hydroxy-2 -deoxyuridine (5-OHdUrd) (23) that are produced from dehydration reactions of 5,6-dihydroxy-5,6-dihydro-2 -deoxycytidine (20) and 5,6-dihydroxy-5,6-dihydro-2 -deoxyuridine (21), respectively. MQ-photosen-sitized oxidation of dCyd also results in the formation of six minor nucleoside photoproducts, which include the two trans diastereomers of AT-(2-de-oxy-/j-D-eryf/iro-pentofuranosyl)-l-carbamoyl-4 5-dihydroxy-imidazolidin-2-one, h/1-(2-deoxy-J8-D-crythro-pentofuranosyl)-N4-ureidocarboxylic acid and the a and [5 anomers of N-(2-deoxy-D-eryfhro-pentosyl)-biuret [32, 53]. In contrast, formation of the latter compounds predominates in OH radical-mediated oxidation of the pyrimidine ring of dCyd, which involves preferential addition of OH radicals at C-5 followed by intramolecular cyclization of 6-hydroperoxy-5-hydroxy-5,6-dihydro-2 -deoxycytidine and subsequent generation of the 4,6-endoperoxides [53]. 

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