2 -deoxycytidine 5 -diphosphate

Cytosine Deoxycytidine Deoxyeytidyiic acid Deoxycytidine. monophosphate (dCMP) Deoxycytidine diphosphate (dCDP) Deoxycytidine triphosphate (dCTP)... 

Cytidylate reductase, the enzyme that reduces cytidine diphosphate to 2-deoxycytidine diphosphate is inhibited not only by 1- -D-arabinofuranosyl-cytosine, but also by 9 -D-arabinofuranosyladenine [330] and 9-/3-D-arabino-furanosylpurine-6( 1 H)-thione (LXXV) [331-333]. 9-Butylthioguanine (LXXVl), which is catabolized to unidentified excretion products but which is not debutylated, blocks the incorporation of adenine into DNA, but the exact mechanism of this action is unknown [334]. 

Raetz, C.R., Kennedy, E.R Function of cytidine diphosphate-diglyceride and deoxycytidine diphosphate-diglyceride in the biogenesis of membrane lipids in Escherichia coll. J Biol Chem 248 (1973) 1098-1105. 

DeoxyribOM phosphates phosphorylated derivatives of the deoxypentose, l-deoxy-n-rihose. They are biosynthesized by reduction of ribose phosphates in the course of nucleotide synthesis There are two enzymes in E. coli which reduce cytidine diphosphate to deoxycytidine diphosphate. Deoxytibose 5- and 1-phosphate form an equilibrium mixture in the presence of phosphopentomutase (EC 2.7.5.6). 

Cytosine Arabinoside (1-B-D-arabinofuranosylcytosine, ara-C, cytara-bine) - Enzymatic phosphorylation studies confirm that ara-C and its phos-phorylated derivatives are deoxycytidine antagonists rather than cytidlne antagonists. 2 inhibition of DNA polymerase activity is considered more significant j-q antlneoplastic properties than either blocking the uptake of thymidine or the inhibition of the conversion of cytidlne diphosphate to deoxycytidine diphosphate. Ara-C rapidly kills S phase cells. It affects the passage rate of cells from S to G2 phase more than from Gl to Sl5. 

While mammahan cells reutilize few free pyrimidines, salvage reactions convert the ribonucleosides uridine and cytidine and the deoxyribonucleosides thymidine and deoxycytidine to their respective nucleotides. ATP-dependent phosphoryltransferases (kinases) catalyze the phosphorylation of the nucleoside diphosphates 2 "-de-oxycytidine, 2 -deoxyguanosine, and 2 -deoxyadenosine to their corresponding nucleoside triphosphates. In addition, orotate phosphoribosyltransferase (reaction 5, Figure 34-7), an enzyme of pyrimidine nucleotide synthesis, salvages orotic acid by converting it to orotidine monophosphate (OMP). 

This enzyme [EC 2.7.1.74] catalyzes the reaction of a nucleoside triphosphate with deoxycytidine to produce a nucleoside diphosphate and dCMP. This enzyme can use any nucleoside triphosphate (except dCTP) as the phosphate-donor substrate and it can phosphorylate cytosine arabinoside as well. 

Gemcitabine is intracellularly activated by nucleoside kinases to diphosphate and triphosphate nucleosides. Gemcitabine diphosphate inhibits DNA synthesis by inhibiting ribonucleotide reductase while gemcitabine triphosphate competes with deoxycytidine triphosphate for incorporation into DNA. Gemcitabine is used for the treatment of non-small cell lung carcinoma and of adenocarcinoma of the pancreas. It has to be administred intravenously and is eliminated by metabolism with an elimination half-life of approximately 50 minutes. Its spectrum of adverse effects is comparable to that of 5-FU. 

Cidofovir (Vistide) is an acyclic phosphonate cytosine analogue with activity against herpesviruses including CMV, HSV-1, HSV-2, EBV, and VZV. It also inhibits adenoviruses, papillomaviruses, polyomaviruses, and poxviruses. Activation of cidofovir requires metabolism to a diphosphate by host cellular enzymes. Because this activation does not depend upon viral enzymes, similar levels of cidofovir diphosphate are seen in infected and uninfected cells. Cidofovir diphosphate competes with deoxycytidine triphosphate (dCTP) for access to viral... 

Cytarabine (ara-C) is an S phase-specific antimetabolite that is converted by deoxycytidine kinase to the 5 -mononucleotide (ara-CMP). Ara-CMP is further metabolized to the diphosphate and triphosphate metabolites, and the ara-CTP triphosphate is felt to be the main cytotoxic... 

Gemcitabine is phosphorylated initially by the enzyme deoxycytidine kinase and then by other nucleoside kinases to the di- and triphosphate nucleotide forms, which then inhibit DNA synthesis. Inhibition is considered to result from two actions inhibition of ribonucleotide reductase by gemcitabine diphosphate, which reduces the level of deoxyribonucleoside triphosphates required for the synthesis of DNA and incorporation of gemcitabine triphosphate into DNA. Following incorporation of gemcitabine nucleotide, only one additional nucleotide can be added to the growing DNA strand, resulting in chain termination. 

An important difference between the two compounds is that azacytidine (2) incorporates into RNA, while decitabine (1) acts on DNA. Within cells, decitabine (1) is phosphorylated by deoxycytidine kinase, and after conversion to decitabine triphosphate, it is incorporated into DNA in place of deoxycytidine triphosphate. Azacitidine (2) is phosphorylated by uridine-cytidine kinase and eventually incorporated into RNA, inhibiting the processing of ribosomal RNA and ultimately protein synthesis. Azacitidine (2) can also inhibit DNMTs when azacytidine diphophate is reduced to decitabine diphosphate, which is further phosporylated by kinases to dcitabine triphosphate and incorporated into DNA. Because of the inefficiency of these extra steps, the hypomethylating potency of 2 is believed to be one fifth to one tenth that of l.6-8... 

DBH, dopamine-(3-hydroxylase dCDP, 2 -deoxycytidine 5 -diphosphate dCMP, 2 -deoxycytidine 5 -monophosphate dCTP, 2 -deoxycytidine 5 -triphosphate dCDP, 2 -deoxyguanosine 5 -diphosphate... 

In gemcitiihine, fluorine atonts replace the hydroxyl group and the hydrogen atom at the 2 position of cytidine."" After its anabolism to diphosphate and triphosphate metabolites, gemcituhine inhibits ribonucleotide mducta.se and competes with 2 -deoxycytidine triphosphate for incorporation into DN A. These effects pnxluce cell-cyclc-specific cytotoxicity. Gemcitabine has become a first-line treatment for liK ally advanced and metastatic adenocarcinoma of the pancreas. 

The deoxycytidine phosphates result from reduction of CDP to dCDP by a mechanism analogous to that described for the purine nucleotides. Then dCDP is converted to dCTP by nucleoside diphosphate kinase. 

The pathway by which the 3, 5 -diphosphate esters of thymidine and 2 -deoxycytidine are formed during acid hydrolysis of 2 -deoxyribonucleic acid is shown in Scheme 27 " Cleavage of the glycosylic linkages to the... 

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