Cytidine 2-deoxy-5 -methyl

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. 

Figure 9.4 Monoterpene biosynthesis in peppermint oil gland secretory cells. The enzymes involved in this pathway are (1) 1-deoxy-D-xylulose 5-phosphate synthase, (2) 2-C-methyl-D-erythritol 4-phosphate reductoisomerase, (3) 2-C-methyl-D-erythritol 4-phosphate cytidyltransferase, (4) 4-(cytidine 5 -diphospho)-2-C-methyl-D-erythritol kinase, (5) 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase, (6) isopentenyl diphosphate isomerase, (7) geranyl diphosphate synthase, (8)...

Figure 6.42 Oxidation of deoxy-5-methylcytosine to deoxythymidine and cytidine to uridine. This may be caused by reactive oxygen species or oxidizing agents such as nitrous acid. d5mC is present in methylated CpG sequences.

More difficulty was encountered with the pyrimidine deoxynucleosides. It was tacitly assumed that the sugar radical in thymidine and deoxy-cytidine, by analogy with the ribonucleosides, is attached to position Nl. The first significant experiment111 to shed some light upon the validity of this assumption was based upon the methylation studies of Levene and Tipson.108 Deoxyribonucleic acid from thymus was methylated with dimethyl sulfate plus alkali, and the product was degraded by strong-acid hydrolysis. One of the products obtained was 3-methylthymine (XI).111 A... 

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).

Hydration of the thymidine radical cation leads to the predominant formation of the oxidizing 6-hydroxy-5,6-dihydrothymid-5-yl radical whereas deprotonation mostly generates the methyl-centered radical (Fig. 4). As already pointed out, these two pyrimidine radicals are also produced upon reaction with OH. However, the methyl-centered radical represented only 5% of base radicals when produced by OH while it corresponds to 30% of the thymidine radicals produced upon one-electron oxidation. Type I photosensitization of 2 -deoxy-cytidine leads to the formation of the 6-hydroxy-5,6-dihydro-2 -deoxycytidil-5-yl radical also produced upon reaction with OH. Additional oxidative pathways involve the formation of 2-deoxyribonolactone and free cytosine as well as production of 2 -deoxyuridine as the result of deprotonation ofthe pyrimidine radical cation at Cl and NH2 group, respectively. 

The photoinduced intramolecular electron transfer reactions of some poly-(ethylene glycol)-linked 9-aminoacridine-benzoate electron donor-acceptor systems have been described. Photosensitized oxidation of 5-methyl-2 -deoxy-cytidine using menadione (2-methylnaphthalene-l,4-dione) gives 5,6-dihydroxy-5,6-dihydro-5-methyl-2 -deoxycytidine in what is thought to be an electron... 

Syntheses involving standard condensation procedures for heterocyclic bases with amino-sugar derivatives have included the preparation of 2 -azido-, 3 -azido-2 ,5 -diazido-, and 3, 5-diazido-derivatives of arabino-nnAinc, 3 -amino-3-deoxy-adenosine, -uridine, and -cytidine 5-phosphates, 2, 3-bis(2-chloroethyl)-aminophosphoryl-3-amino-3-deoxyadenosine (which has anti-tumour activity), 3-A -methyl-A -nitrosoureido-3-deoxy-adenosine and the corresponding 5-substituted isomer, and 2 -azido-2-deoxy- and 2-amino-2-deoxy-D-arabinofuranosyl-... 

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. 

Nudeosides, Nudeotides, and their Derivatives.—Uridine, uridine 5 -(niethyl oxyacetate), 6-chloro-9-j8-D-ribofuranosylpurine, 6-methyl-9-j8-D-ribofurano-sylpurine, 5-acetyl-l-(3,5-0-isopropylidene-j8-D-xylofuranosyl)uracil, 2 -de-oxycytidine, the 1 1-complex of cytidine and iV-benzyloxycarbonylglutamic acid, l-(3-0-methyl-j8-D-arabinofuranosyl)cytosine, 2 -deoxyadenosine 5 -(sodium phosphate), 9-j8-D-arabinofuranosyladenine hydrochloride, 8-j8-D-ribofuranosyladenine, 8 - (2 - deoxy - oc - d - erythro - pentofuranosyl) - 6 -hydroxy-purine, l-methyl-4-jS-D-erythrofuranosyl-4-imida2oline-2-thione, and 4,6-di-0-acetyl-l,3 -anhydro-2,3-dideoxy-3-[3-hydroxy-5-methyl-(2if)-l,2,6-thiadiazin-2-yl l,l-dioxide]-a-D-n 6o-hexopyranose (455). ... 

Among derivatives based on the stucture of biological compound, one may recall studies on the photochemistry of 4 -azido-2 -deoxy-2 -methyl-cytidine, and on 6-azidopurine ribonucleoside in water. 

There have been many reports of syntheses of deoxy nucleosides by standard sugar-base condensation reactions. These include 5 -deoxy-ribo nucleosides and 5 -mono- or 5",5-di-deuterated analogues, as well as derivatives of 5-deoxy-D-xylose and 5-deoxy-D-glucose, 5-alkylated thymidine derivatives, 2 -deoxy-6-methyl-5-azacytidine and its a-anomer, the thymidine analogue 4-(2-deoxy-B-D-erythro-pento-furanosyl)-6-methyl-l,2,4-triazine 3(HH)-one-1-oxide, 6-aza-3-deaza analogues of 2 -deoxy-cytidine and 2 -deoxyuridine,3 -deoxycytidine from a 3-deoxy-ribofuranose obtained from a fermentation broth producing the 3 -deoxy nucleoside antibiotic, cordycepin, 4-deoxy-DL-threo-pentopyranosyl pyrimidine nucleosides, and 5 -C-methyluridines derived from 6-deoxy-D-allose and 6-deoxy-D-talose. A range... 

Deoxy-2 -C-methyl-ara-cytidine (27) has been synthesized from a keto-nucleoside precursor as shown in Scheme 6. ... 

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