Natural nucleosides

In biological fluids and tissues. The value of HPLC in the analysis of nucleosides in biological tissues and fluids arises from the 

Relatively few papers have reported the estimation of nucleosides in animal cells using HPLC. However, the metabohc state of cells can be determined in this way and this allows the progress of certain diseases to be monitored (Nissinen, 1980). A recent determination of nucleosides in cell extracts was carried out after initial acid precipitation, neutrahsation and centrifugation followed by chromatography on a reversed phase Cjg column using an aqueous sodium acetate-acetonitrile mobile phase (Harmenberg, 1983). 

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Some of them were obtained for the first time by an enzymatic procedure which, of course, can result only in the aza analogs of natural nucleosides, i.e., ribofuranosyl-6-azauracil (6-azauridine) (75) and 2 -deoxyribofuranosyl-6-azathymine (6-azathymidine). The first of these was prepared by Skoda et ai. and a modification of their procedure was used by Handschumacher, In this way it is possible to obtain the crystalline nucleoside on the large scale. 

Lamivudine (also known as Epivir and 3TC) is a potent antiviral drug used in the treatment of HIV and hepatitis B virus (HBV) infections. Although both enantiomers are equipotent antiviral agents, the unnatural enantiomer (with respect to natural nucleosides) is far less cytotoxic, and so a method of selectively accessing the single enantiomer was required. 

These substances are analogues of thymine (azidothymidine, stavudine), adenine (didanosine), cytosine (lami-vudine, zaldtabine), and guanine (car-bovir, a metabolite of abacavir). They have in common an abnormal sugar moiety. Like the natural nucleosides, they undergo triphosphorylation, giving rise to nucleotides that both inhibit reverse transcriptase and cause strand breakage following incorporation into viral DNA. 

The sarcoplasmic transport system can be fueled in addition to ATP by a great number of phosphate compounds which differ considerably in their chemical nature. Not only the natural nucleoside triphosphates126 but also para-nitrophenylphosphate,27 acetyl phosphate128 or carbarmyl phosphate129 can drive calcium transport. While there are considerable differences between the rates with which calcium transport proceeds with the different substrates, they are all used with the same coupling ratio of two and the pump can establish similar maximal concentration ratios (Fig. 7)... 

Thus, O-glycosyl trichloroacetimidates exhibit in terms of ease of formation, stability, reactivity, and general applicability outstanding glycosyl donor properties they resemble in various aspects the natural nucleoside diphosphate sugar derivatives. Thus, this method has become a very competitive alternative to the existing techniques. 

Drugs that act as nucleoside analogues mimic the activity of nucleosides while lacking full function. Because nucleoside analogues structurally resemble natural nucleosides, the analogues (1) do not passively diffuse across a membrane and (2) can readily hitch a ride across the membrane by means of an ENT and/or a CNT. Several nucleoside analogues and their corresponding carrier proteins are shown in Table 3.8.14... 

Natural nucleosides, mass-spectrometric structural characteristics 91 ACR81. 

It looks as if the more nucleophilic end of the azide has attacked the wrong end of the alkyne but we must remember that (1) it is very difficult to predict which is the more nucleophilic end of a 1,3-dipole and (2) it may be either HOMO (dipole) and LUMO (alkyne) or LUMO (dipole) and HOMO (alkyne) that dominate the reaction. The reason for doing the reaction was to make analogues of natural nucleosides (the natural compounds are discussed in Chapter 49). In this case the OH group was replaced by a cyanide so that a second aromatic ring, a pyridine, can be fused on to the triazole. 

A C2 symmetric bis(amidophosphine) ligand was used by Trost to prepare the natural nucleoside adenosine (see Chapter 49 for nucleosides) in similar fashion to the carbocyclic analogue described above. The key enantioselective step was the first allylic alkylation that selected between two cnan-tiotopic benzoates in the meso dihydrofuran derivative to give one enantiomer the expected cis product. 

Modified nucleosides have proved to be among the best antiviral compounds. The most famous anti-AIDS drug, AZT (zidovudine from Glaxo Wellcome), is a slightly modified DNA nucleoside (3 -azidothymidine). It has an azide at C3 instead of the hydroxyl group in the natural nucleoside. 

When AIDS (Acquired Immune Deficiency Syndrome) first came into the news in the 1980s it was a horror story of mysterious deaths from normally harmless diseases after the patient s immune system had been weakened and eventually destroyed. The cause was identified by biologists as a new virus HIV (Human Immunodeficiency Virus) and antiviral drugs, notably AZT (Chapter 49), were used with some success. These drugs imitate natural nucleosides (AZT imitates deoxythymidine) and inhibit the virus from copying its RNA into DNA inside human cells by inhibiting the enzyme reverse transcriptase . 

The synthesis of the target ON conjugate 5 -XTCTCACTACCTCTT (X = 2.72, Fig. 2.20) was performed using the SP phosphoramidite protocol with PNT (N-pent-4-enoyl)-protected phosphoramidites 2.69 and 2.70, the unprotected phosphoramidite 2.71, and the conjugated phosphoramidite 2.72 (147). Their structure and synthesis (76) from natural nucleosides is reported in Fig. 2.20. The protection of the base was... 

A swap of the methyl carbon with nitrogen in aza-AdoMet leads to sinefungin (see Fig. 2g)—a natural nucleoside antibiotic found in Streptomyces griseolus. Such reverse chemistry additionally enhances the chemical stability of cofactor. Because of the positive charge of the protonated amine and correct chirahty at the carbon center, sinefungin has an extremely high inhibitory potential for AdoMet-dependent methyltransferases. 

Synthesis of glycopyranosylphosphonate analogues of certain natural nucleoside diphosphate sugars as potential inhibitors of gly-cosyltransferases. J. Med. Chem. 1987 30 1383-1391. 42. 

Oligonucleotides with extended zwitterionic internucleotide linkages have been synthesised using two non-natural nucleosidic analogues, N-(2-hy-... 

Extensive work has been reported on the chemistry of polyphosphates, in particular that of dinucleoside and sugar nucleoside pyrophosphates. This reflects the reliability and flexibility of the phosphoramidate methods which have been developed over the past few years. Similarly, a wide range of oligonucleotide building blocks, incorporating extensive structural modifications when compared to the natural nucleoside structures, have been described. 

Because of their structural resemblance to natural nucleosides, these substances are integrated into the newly synthesized DNA strand by the enzymes of DNA synthesis (e.g. DNA polymerase, reverse transcriptase) in place of the natural nucleosides. The outcome is chain break. Virus mutation, however, may reduce the effectiveness of nucleoside analogue. The clinical import-... 

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