Nucleoside and nucleotide analogues

All the nucleoside (and nucleotide) analogues that have entered the clinic for the treatment of HBV infections (i.e., nucleoside analogues lamivudine, entecavir, tel-bivudine nucleotide analogues adefovir and tenofovir) are fairly well tolerated without side effects that would preclude their long-term usage. The nucleoside analogues in (pre)clinical development for the treatment of HCV infections are not yet sufficiently advanced to assess their tolerability and/or safety. 

Gallant JE, Gerondelis PZ, Wainberg MA, Shulman NS, et al. 2003. Nucleoside and nucleotide analogue reverse transcriptase inhibitors A clinical review of antiretroviral resistance. Antivir Ther. 8 489-506. 

FIGURE 6.22 Other nucleoside and nucleotide analogue antivirals... 

Fig. 2.4 Structures and properties of selected nucleoside and nucleotide analogues.

Fung SK, Lok AS. Drug insight nucleoside and nucleotide analogue inhibitors for hepatitis B. Nat Clin Pract Gastroenterol Flepatol 2004 1 90-97. 

Jordheim LP, Durantel D, Zoulim E, Dummitet C (2013) Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases. Nat Rev Drug Discovery 12 447 164... 

Nucleoside and nucleotide analogues have been widely used in the treatment of various diseases. Koegler et al. reported the synthesis of 6-aza-2 -deo3qruridine monophosphate analogues (6). These compounds can inhibit thymidylate synthases, and also act as substrates or inhibitors of thymidine monophosphate kinase in mycobacterium tuberculosis. 

Nucleoside and nucleotide reverse transcriptase analogues (NRTI) lack a 3 hydroxyl group and as a result no additional nucleotides can be incorporated into the growing DNA chain. Two NRTI resistance mechanisms are identified impairment of the incorporation of the antiretroviral drug (discrimination) and removal of the analogue from the terminated DNA chain (excision) as reviewed in Chap. 3 (Arion et al. 1998 Meyer et al. 1999 Saralianos et al. 1999). 

Potentially tautomeric pyrimidines and purines are /V-alkylated under two-phase conditions, using tetra-n-butylammonium bromide or Aliquat as the catalyst [75-77], Alkylation of, for example, uracil, thiamine, and cytosine yield the 1-mono-and 1,3-dialkylated derivatives [77-81]. Theobromine and other xanthines are alkylated at N1 and/or at N3, but adenine is preferentially alkylated at N9 (70-80%), with smaller amounts of the N3-alkylated derivative (20-25%), under the basic two-phase conditions [76]. These observations should be compared with the preferential alkylation at N3 under neutral conditions. The procedure is of importance in the derivatization of nucleic acids and it has been developed for the /V-alkylation of nucleosides and nucleotides using haloalkanes or trialkyl phosphates in the presence of tetra-n-butylammonium fluoride [80], Under analogous conditions, pyrimidine nucleosides are O-acylated [79]. The catalysed alkylation reactions have been extended to the glycosidation of pyrrolo[2,3-r/]pyrimidines, pyrrolo[3,2-c]pyridines, and pyrazolo[3,4-r/]pyrimidines (e.g. Scheme 5.20) [e.g. 82-88] as a route to potentially biologically active azapurine analogues. 

Hattori H, et al. Nucleosides and nucleotides. 158. l-(3-C-ethynyl-P-D-ribo-pentofuranosyl)-cytosine, 1 -(3-C-ethynyl-P-D-ribo-pentofuranosyl)uracil, and their nucleobase analogues as new potential multifunctional antitumor nucleosides with a broad spectrum of activity. J Med Chem 1996 39 5005. 

Schneider and coworkers investigated the capability of the tetraazonia cyclophane 51 to bind nucleosides and nucleotides in water [72]. Its two diphenylmethane units border a lipophilic cavity for the uptake of likewise lipophilic molecules or subunits. As evidenced by HNMR studies of the complexes, only in the case of the purine derived nucleosides and nucleotides (A, G, AXP, GMP) the base moiety is included inside the host cavity but not in the case of the pyrimidine analogues (U, C, UMP, CMP, TMP). Due to their hydrophilic nature, the sugar and phosphate groups remain outside the niche. 

The assignments of the purine resonances [460, 749, 751, 758, 759, 761] of proton broadband-decoupled 13C NMR spectra of nucleosides and nucleotides are made using the following aids [749, 761] Correlation with the signals of the parent bases and analogous nucleosides or nucleotides comparison of the 13C NMR spectrum with that of a specifically analogue correlations of the chemical shift values with the 7r-electron densities [749, 761] and, in addition, proton off-resonance decoupling, which affords the identification of quaternary carbon atoms. 

The facile reaction of CAA and BAA with nucleosides and nucleotides is one example of many of the applications of the bifunctional reactivity of halogenated aldehydes and ketones in modification of biomolecules. In an early example of the extensive use of halogenated ketones as protease substrate analogues, l-V-tosylamido-2-phenylethyl chloro-methyl ketone (TPCK) 30 was synthesized as a chymotrypsin substrate analogue. Stoichiometric inhibition was accompanied by loss of one histidine residue as a result of alkylation by the chloromethyl moiety68. A host of similar analogues were subsequently prepared and used as selective enzyme inhibitors, in particular for the identification of amino acid residues located at enzyme active sites69. 

A large number of halogenated analogues are among the multitudinous synthetic nucleosides and nucleotides that have been prepared in the search for effective antiviral and antitumor agents. A comprehensive survey of this field is beyond the scope of this chapter. Selected examples will be given with an emphasis on the biochemical rationales involved. 

The facility with which the bromo, chloro and iodo analogues undergo reduction, with maintenance of the 5,6-double bond and replacement of the halogen by hydrogen, has been exploited for the electrochemical synthesis of 5-(3H)-uracil by conducting the reaction in tritiated water121). This procedure should be equally effective for the synthesis of labelled uracil nucleosides and nucleotides. 

An additional characteristic, common to all purine analogues, and ascribed to the presence of the imidazole ring is the strong adsorption of adenine and its nucleosides and nucleotides at the electrode surface35 37 53, 153), with a standard free energy for adsorption of 29-38 kJ/M 37,53). 

New Protecting Groups in Nucleoside and Nucleotide Chemistry. Pfleide-rer, W. Schirmeister, H. Reiner, T. Pfister, M. Charubala, R. In Biophosphates and their Analogues—Synthesis, Structure, Metabolism and Activity Bruzik, K. S Stec, W. J., Eds. Elsevier Amsterdam, 1987, pp 133-142. 

Marquez, V. E. (1989) Design, synthesis, and antiviral activity of nucleoside and nucleotide analogs. Nucleotide Analogues Antiviral Agents, ACS Symposium Series 401, pp. 140-155. 

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