2-Deoxy-5-cytidine monophosphate

A-Acetyl-9-deoxy-9-fluoroneuraminic acid (591) was prepared by treatment of a protected 6-hydroxyl precursor with A, A-diethylaminosulfur trifluoride (DAST) or through condensation of 2-acetamido-2,6-dideoxy-6-fluoro-D-mannopyranose with potassium di(/ >r/-butyl) oxaloacetate. Compound 591 is a substrate for cytidine monophosphate (CMP)-sialic acid synthetase, giving rise to CMP-5-A-acetyl-9-deoxy-9-fluoroneuraminic acid, which is cytotoxic against tumor cells. 5-A-Acetyl-3-fluoroneuraminic acids 592-594 were prepared through fluorine (or acetyl hypofluorite) addition (in AcOH) to methyl 5-acetamido-4,7,8,9-tetra-0-acetyI-2,6-anhy-dro-2,3,5-trideoxy-D- /ycm>D- a/arto-non-2-enopyranosate. Compound 592 was found to be a potent neuraminidase inhibitor. 

Li de La Sierra, I.M. Gallay, J. Vincent, M. Bertrand, T. Briozzo, P. Barzu, O. Gilles, A.M. Substrate-induced fit of the ATP binding site of cytidine monophosphate kinase from Escherichia coli time-resolved fluorescence of 3 -anthraniloyl-2 -deoxy-ADP and molecular modeling. Biochemistry, 39, 15870-15878 (2000)... 

CMP, 3-deoxy-i>g/>>ceroD-ga/a 7ononulo-sonic add cytidine monophosphate-3-deoxy-D-gIycero-D-galaclo-nonu osomc acid 0.5 26 PK 20 NK 1.2 CS 18 69... 

Sialyl residues in oligosaccharides are introduced by the reaction of cyti-dine monophosphate-V-acetylneuraminic acid (49) as the sugar donor with the appropriate substrate, in the presence of specific transferases. Three of these have been utilized in syntheses which may be considered to be preparative. None are readily available. The most common, which we have called STA (see Table I), catalyzes the transfer of a 5-acetamido-3,5-di-deoxy-D-g/ycm>-a -D-ga/arfo-2-hexulopyranosonic acid unit (the a-D-pyra-nose form of JV-acetylneuraminic acid) to the primary position of D-galactose in a JV-acetyllactosamine residue.86 This enzyme also transfers vV-acetyl-9-O-acetylneuraminic acid (20) and V-glycolylneuraminic acid (12) from the corresponding cytidine monophosphate derivatives.16 The commercial enzyme is rather expensive, but pork liver from a butcher is a... 

Under basic conditions (0.2 M barium hydroxide, 100°, 30 minutes), the nucleoside 3 5 -cycIic phosphates are converted into the 3 - and 5 -phosphates in the ratio of about 5 1. For cytidine 3 5 -cyclic phosphate, some concomitant deamination to the uridine nucleotide analogs is also observed (as noted with cytidine 3 -phosphate), so that the nucleotides obtained are similar to those found in the alkaline hydrolyzate of uridine 3 5 -cyclic phosphate. In addition, one of the nucleotides obtained in these hydrolyzates differs from the 3 - or 5 -phosphates in its ion-exchange chromatographic behavior. The presence of an unidentified nucleoside monophosphate in small proportion was also observed when 2 -deoxy-cytidine 3 5 -cyclic phosphate was hydrolyzed with barium hydroxide under similar conditions. 

FIGURE 2.3 Representativemassspectrafortheieactionofdeprotonated2-deoxy-5-cytidine monophosphate (5-dCMP) with D2O in a quadrupole-ion trap. Reaction times are (a) 0 ms, (b) 250 ms, (c) 2000 ms, and (d) 10,000 ms. Peaks are labeled as D , where n equals the number of incorporated denterinm atoms. (Reproduced from Chipuk, J.E. Brodbelt, J.S. J. Am. Soc. Mass Spectrom. 2007,18, 724-736. With permission from Elsevier.)... 

The nucleotides are 2-deoxyadenosine 5 -monophosphate (dAMP), 2-deoxythymidine 5 -monophosphate (dTMP), 2-deoxyguanosine 5 -monophosphate (dGMP), and 2-deoxy-cytidine 5 -monophosphate (dCMP). 

Among nucleoside glycosyl monophosphates, the primary derivatives include cytidine (N-acetyl neuraminic monophosphate) (CMP-NeuAc),51 in which the n-glycero-fi-n-galacto configuration of the monosaccharide group has been confirmed,52 and the analogous derivative of 3-deoxy-D-manno-2-octulosonic acid.53,54... 

The de novo pathway to 2 -deoxythymidine monophosphate (dTMP) synthesis first requires the use of dUMP (2 -deoxyuridine-5 -monophosphate) from the metabolism of either UDP or CDP (cytidine diphosphate). The hydrolysis of dUTP (2 -deoxyuridine-5 -triphosphate) to dUMP and subsequent methylation at C-5 by the action of thymidylate synthase, using A, A i°-methylenetetrahydrofolate (THF) as the methyl donor, generate dTMP (Figure 6.54). The latter is subsequently phosphorylated to deoxy-thymidine triphosphate (dTTP) used in DNA synthesis and repair. 

Closely related to ATP, and present in biological systems, are a number of other nucleoside triphosphates and their corresponding diphosphates and monophosphates. These are uridine triphosphate (UTP), cytidine triphosphate (CTP), guanosine triphosphate (GTP), and thymidine triphosphate (TTP), all of which have about the same free energy of hydrolysis as ATP (11.29). In addition there are the deoxy nucleoside triphosphates (Chapter 10.4). 

Cytidine phosphates cytidine S -monophosphate (CMP, cytidylic acid, M, 323.2), cytidine 5 -diphos-phate (CDP, M, 403.19) and cytidine 5 -triphosphate (CTP, M, 483.16). For structure, see e. g. Pyrimidine biosynthesis. CTP is a precursor of RNA synthesis, while deoxy-CTP is a precursor of DNA synthesis. CDP may be regarded as the coenzyme of phospholipid biosynthesis (see Membrane lipids) (activated choline is CDP-choline). Glycerol and the sugar alcohol, ribitol, are also activated by bonding to CDP (see Nucleoside diphosphate sugars). Reduction of ribose... 

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