Nucleoside agents

The nucleoside agents do not have clinically significant drug interactions with the standard antituberculosis medications. However, the Pis and NNR-TIs may inhibit or induce cytochrome P-450 isoenzymes (CYP450) and thus, these drugs may alter the serum concentration of the rifamycins (Table 17(a) and (b)). 

W.A. Tao et al., Rapid enantiomeric quantification of an antiviral nucleoside agent (d, l-FMAU, 2 -fluoro-5-methyl-, d, L-arabinofuranosyluracil) by mass spectrometry. J. Med. Chem. 44, 3541-3544 (2001)... 

Resistance Viral isolates from patients who have undergone prolonged therapy with ddl contain reverse transcriptase with amino acid substitutions. Cross-resistance with the other nucleoside agents has not been reported. 

Another dideoxypyrimidine nucleoside active against human immunodeficiency vims is 3 -azido-2/3 -dideoxyuridine [84472-85-5] (AZDU or CS-87, 64) C H N O. Since its synthesis, (167) CS-87 has been identified as a promising antiHIV agent (168) and is currentiy undergoing phase I clinical trials in patients with AIDS and AIDS-related complex. It appears to be less potent than AZT against HIV in a peripheral blood mononuclear (PBM) cell screening system and in MT-4 cell lines. This lower activity in PBM cells appears to be related to a lower affinity of CS-87 for the enzyme responsible for its initial phosphorylation (169). However, CS-87 has significantly lower toxicity on bone marrow cells than AZT (170) and penetration of the CNS as a 5 -dihydropyridine derivative. 

The search for new antivkal agents is ongoing and extensive not all vimses have been included here, and new vimses pathogenic to humans will continue to be identified. Novel nucleosides as weU as nonnucleosidic compounds which possess greater potency and enzymic specificity for the future treatment of both acute and persistent human vkal infection will continue to be discovered. 

A two-component sugar-base unit is called a nucleoside, eg, adenosine. Nucleosides and their derivatives are important pharmaceutically (see Antibiotics, NUCLEOSIDES AND NUCLEOTIDES ANTIVIRAL AGENTS). 

Nucleoside antibiotics biosynthesis, 1, 88-90 Nucleosides oxa analogues, 3, 1085 as pharmaceuticals, 1, 153 protected, 5, 316 Nucleosidin occurrence, 5, 603 Nupharolutine synthesis, 2, 393 Nybomycin applications, 6, 667 Nybomycin, deoxy-applications, 6, 667 Nystatin antifungal agent veterinary use, 1, 211... 

Azauridine was also synthesized using the knowledge of the course of alkylation of 6-azauracil 2-methylmercapto derivatives (e.g., Section II,B,4,b). The 1-ribofuranosyl derivative obtained by reaction of the mercury salt of the 2-methylmercapto derivative with tri-O-benzoyl-jS-D-ribofuranosyl chloride on removal of the methyl-mercapto and then benzoyl groups yielded crystalline 6-azauridine, The main difference between uracil and 6-azauracil nucleosides consists in the preparation of cyclic nucleosides. It is known that uridine can be readily converted to cyclic nucleosides by the reaction of 2 (50-O-mesyl derivatives with nucleophilic agents, Analogous... 

Derivatives of 3-oxo-l,2,4-triazine 1-oxide undergo alkylation with various alkylating agents. Thus the reaction of 3-methoxy-l,2,4-triazine 1-oxide 20 with 2,3,5-tii-(9-benzoyl-/3-D-ribofuranosyl bromide, followed by the removal of the benzoyl protection with sodium methoxide, leads to an abnormal nucleoside 4-(/3-D-iibofuranosyl)-l,2,4-triazin-3(4//)-one 1-oxide 21 (73JOC3277). 

Compounds prepared from naturally occurring nucleosides are of course more closely related to genetic material and may have a better chance of interacting with infected cells. Mercu-ration of the 2 -dcoxyuridine 113 leads to the organometallic derivative 114 reaction of that with ethylene in the presence dilithio palladium tetrachloride gives the alkylation product 115 this is reduced catalytically in situ. There is thus obtained the antiviral agent edoxudine (116) [25]. 

Nucleoside analogs substituted at the C-5 position of the pyrimidine base have been identified as anfiviral and anticancer agents, hi this context new... 

Mitochondria-associated toxicities, such as pancreatitis, are frequently demonstrated in HlV/HCV-coinfected individuals, and may significantly influence treatment options (de Mendoza and Soriano 2005). Yet, no cell culture or animal models have been developed to predict nucleoside-induced pancreatitis. Nevertheless, an association of HCV replication and mitochondrial DNA depletion in primary human lymphocytes obtained from HIV/HCV-coinfected individuals under concomitant administration of HCV and HIV medications was demonstrated by de Mendoza and coworkers (de Mendoza et al. 2007). They claimed that the use of HCV medication together with certain antiretroviral agents seemed to enhance mitochondrial damage due to a synergistic deleterious interaction between the anti-HCV and anti-HIV drugs. In contrast, an improvement in mitochondrial content with effective... 

Hurwitz SJ, Schinazi RF (2002) Development of a pharmacodynamic model for HIV treatment with nucleoside reverse transcriptase and protease inhibitors. Antiviral Res 56 115-127 Hurwitz SJ, Tennant BC, Korba BE, Gerin JL, Schinazi RF (1998) Pharmacodynamics of (—)-beta-2, 3 -dideoxy-3 -thiacytidine in chronically virus-infected woodchucks compared to its pharmacodynamics in humans, Antimicrob Agents Chemother 42 2804-2809 Hurwitz SJ, Otto MJ, Schinazi RF (2005) Comparative pharmacokinetics of Racivir, (+/-)-beta-2, 3 -dideoxy-5-fluoro-3 -thiacytidine in rats, rabbits, dogs, monkeys and HIV-infected humans, Antivir Chem Chemother 16 117-127... 

Pierra C, Benzaria S, Amador A, Moussa A, Mathieu S, Storer R, GosseUn G (2005) Nm 283, an efficient prodrug of the potent anti-HCV agent 2 -C-methylcytidine, Nucleosides Nucleotides Nucleic Acids 24 767-770... 

---