Cytosine 3 ,5 -diphosphate

AFCYDP. 2,2 -Anhydro-1 -/ -D-arabinofuranosyl-cytosine-3, 5 -diphosphate monohydrate... 

Reactions (2) and (3) would be similar to those leading to the formation and transformation of cytosine diphosphate-choline 106) or uridine diphosphate 107). It is conceivable, of course, that the reduction of the pento l group to ribityl does not occur with the free pentose phosphate as pictured [reaction (1)], but by a mechanism involving the conversion of a cystosine diphosphate-pentose to cytorine diphosphate-ribitol. This type of reaction would be distantly related to reactions such as the oxidation of uridine diphosphate-glucose to uridine diphosphate-glucuronic acid 108,109). 

Figure 12 Gradient separation of bases, nucleosides and nucleoside mono- and polyphosphates. Column 0.6 x 45 cm. Aminex A-14 (20 3 p) in the chloride form. Eluent 0.1 M 2-methyl-2-amino-l-propanol delivered in a gradient from pH 9.9-100 mM NaCl to pH 10.0-400 mM NaCl. Flow rate 100 ml/hr. Temperature 55°C. Detection UV at 254 nm. Abbreviations (Cyt) cytosine, (Cyd) cytidine, (Ado) adenosine, (Urd) uridine, (Thyd) thymidine, (Ura) uracil, (CMP) cytidine monophosphate, (Gua) guanine, (Guo) guanosine, (Xan) xanthine, (Hyp) hypoxanthine, (Ino) inosine, (Ade) adenosine, (UMP) uridine monophosphate, (CDP) cytidine diphosphate, (AMP) adenosine monophosphate, (GMP) guanosine monophosphate, (IMP) inosine monophosphate, (CTP) cytidine triphosphate, (ADP) adenosine diphosphate, (UDP) uridine monophosphate, (GDP) guanosine diphosphate, (UTP) uridine triphosphate, (ATP) adenosine triphosphate, (GTP), guanosine triphosphate. (Reproduced with permission of Elsevier Science from Floridi, A., Palmerini, C. A., and Fini, C., /. Chromatogr., 138, 203, 1977.)...

ADCC ADP AM ara-C ATP BAPTA antibody-dependent cellular cytotoxicity adenosine diphosphate acetoxymethyl ester cytosine arabinoside adenosine triphosphate bis- (o-aminophenoxy)-ethane-N,N,N, N -tetraacetic acid... 

Cytosine Cytidine Cytidylic add Cytidine monophosphate (CMP) Cytidine diphosphate (CDP) Cytidine triphosphate (CTP)... 

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]. 

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. 

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... 

Cidofovir is a cytosine nucleotide analog with in vitro activity against CMV, HSV-1, HSV-2, VZV, EBV, HHV-6, HHV-8, adenovirus, poxviruses, polyomaviruses, and human papillomavirus. In contrast to ganciclovir, phosphorylation of cidofovir to the active diphosphate is independent of viral enzymes. After phosphorylation, cidofovir acts both as a potent inhibitor of and as an alternative substrate for viral DNA polymerase, competitively inhibiting DNA synthesis and becoming incorporated into the viral DNA chain. Isolates with resistance to cidofovir have been selected in vitro these isolates tend to be cross-resistant with ganciclovir but retain susceptibility to foscamet. Clinically significant resistance to cidofovir has not been reported to date. 

Acetyl-CoA ADP Ala AMP ATP BHK CC9C10 CHO CHSE CMP-NANA CoQ CoQH2 DNA acetyl-coenzyme A adenosine diphosphate alanine adenosine monophosphate adenosine triphosphate baby hamster kidney cell line hybridoma cell line Chinese hamster ovary cell line Chinook salmon embryo cell line cytosine monophosphate-N-acetylneuraminic acid coenzyme Q dihydroubiquinone deoxyribonucleic acid... 

Thus, uridine-cytidine kinase converts uridine and cytidine to UMP and CMP, respectively thymidine kinase converts thymidine to dTMP and adenosine kinase converts adenosine to AMP. Specific kinases convert monophospho-nucleotides to dinucleotides using ATP as a phosphate donor. The conversion of diphosphonucleotides to triphosphonucleotides is carried out by a nonspecific nucleoside diphosphate kinase. This includes both the ribo- and deoxy-ribonucleotides. Cytosine and its nucleoside and nucleotide transformations are often associated with the metabolism of uracil and its nucleosides and nucleotides. Note that UTP can give rise to CTP (Figure 10.9), and also that, in the presence of cytidine deaminase, cytidine can be converted to uridine. 

The biosynthesis of uracil proceeds via decarboxylation of orotidin-5 -phosphate, which is formed from carbamoyl phosphate and aspartate via orotate after nucleosidation with 5-phosphoribosyl-l-diphosphate. Uracil can also be generated from cytosine by oxidative deamination using sodium hydrogensulfite. 

In the cytosol, these monosaccharides can be phosphorylated and subsequently coupled with nucleotides such as uridine diphosphate (e.g., UDP-GlcNAc), guanosine diphosphate (e.g., GDP-mannose), or cytosine monophosphate in the case of sialic acids (Fig. 2b) to create a set of high energy building blocks for glycan assembly. In some cases, such as for the initial steps... 

The a-phosphonolactones, (60) and (61), analogues of cytidine and cytosine arabinoside diphosphates, have been synthesized in an attempt to bypass... 

Cidofovir is an acyclic nucleotide analogue of the monophosphate of cytosine. When phosphoiylated by host cellular enzymes, the active compound cidofovir diphosphate has broad activity against the herpes viruses, including CMV, HSV 1 and 2, VZV, Epstein-Barr virus, and the BK polyomavirus. Cidofovir has primarily been used in the treatment of CMV retinitis in patients who have failed treatment with ganciclovir or foscarnet and in acyclovir-resistant herpes simplex infections. More recently, there is also a growing experience with the use of this medication in kidney transplant patients who have BK virus-associated nephropathy [31], although this interest has been dampened by significant toxicity and only modest clinical activity [32]... 

The syntheses of the 5 -phosphoramidates and 5 -diphosphates of 2 -0-allyl-P-D-arabinofuranosyl-uracyl, -cytosine and adenine (96) have been described. 

TTP synthesis and chemotherapy. rNDP stands for the four ribonucleoside diphosphatesadenosine, cytosine, guanosine, and uridine diphosphate. dNDP stands for the corresponding four deoxyrihonucleoside diphosphates. dNTP stands for the four... 

---