Nucleosides and Nucleoside Analogues

Nucleosides and Nucleoside Analogues.- Kinetin ribonucleoside, 7 l,N -etheno-adenosine,75 2 -deoxy-2 -fluoro-cytidine and 2 -deoxy-2 -fluoro-uridine,75 2,2 -cyclocytidine hydrochloride,7 5  

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Furata, H., Furata, K., Sessler, J. L. (1991). Enhanced transport of nucleosides and nucleoside analogues with complementary base-pairing agents, J. Am. Chem. Soc., 113 4706. 

SLC28A3 CNT3 Mammary gland, pancreas, bone marrow, trachea, intestine, liver, lung, placenta, prostate, testis, brain, heart Nucleosides and nucleoside analogues Na free buffer ... 

C-6 Phosphonylated purine nucleosides [31a-e] were obtained by simple and catalyst free SNAr-Arbuzov reaction of trialkylphosphite and chlor-opurine nucleosides and nucleoside analogues. Higher yields were achieved when the reaction times were shortened and microwave irradiation conditions were applied. 

Octosyl Acids. Three octosyl uronic acid nucleosides, produced by S. cacaoi sub sp. asoensis are shown in Figure 3. The biosynthesis of (172) and (173) has been reported (1). The replacement of the pyrimidine chromophore of (171) with adenine results in a nucleoside analogue that is a competitive inhibitor of cAMP. 

Purine Nucleoside Derivatives. A number of purine nucleoside analogues are also found to be active against several DNA vimses (Fig. 3). The clinically active antiviral drug ara-A (9-P-D-arabinofuranosyladenine [5536-17-4] vidarabine, 23) is active against a number of DNA vimses in vivo and also inhibits certain RNA tumor vimses which repHcate through a DNA intermediate (43). Ara-A, was first synthesized in 1960 (44) and later... 

Phosphonylmethoxyethyl)adenine [106941-25-7] (PMEA, 65) (173), synthesized in 1987 (174), is foremost among the acycHc nucleoside analogues proven to be effective inhibitors of HIV-1 repHcation. The in vitro potency and selectivity of PMEA is comparable to the antiHIV-1 potency and selectivity of 2, 3 -dideoxy-adenosine (175). Although less potent than AZT in vitro PMEA, CgH22N 04P, is markedly more potent than AZT as an in vivo inhibitor of retrovims repHcation (176). In fact, PMEA has proven efficacious in the treatment of murine, feline, and simian retrovims infections in mice, cats, and monkeys, respectively. 

HBV infection remains a major worldwide public health problem. The World Health Organization estimates that there are still 350 million chronic carriers of the vims, who are at risk of developing chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. The success of IFN-a treatment - mainly performed as combined treatment with adenine-arabinoside - has been measured by the normalization of liver enzymes, loss of HBe antigen and of detectable viral DNA in the serum of patients. It has been estimated from several clinical trials that as many as 40% of treated HBV patients would respond to therapy with IFN-a or combined treatment with nucleoside analogues and IFN-a. 

This approach offers unique opportunities for the generation of multi-functionalized cyclic 2-azadiene systems. A wide variation of the substitution pattern at the positions N-1 and C-6 can be determined by an appropriate choice of the aldehyde and amine. Various substituents can easily be introduced at the C-3 position via addition/elimination reactions on the sensitive imidoyl chloride moiety [24]. Upon reaction with bi-functional reagent, an adequately AT-protected 2(lH)-pyrazinone was elaborated into C-nucleoside analogues (Scheme 8). The desired skeleton and functionalities were obtained by oxidation-cyclization reaction followed by photochemical removal of the protective o-nitrobenzyl group [25]. 

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. 

In addition to the NRTI lamivudine (3TC) and the NtRTI adefovir dipivoxU and tenofovir disoproxil fumarate (which has been recently licensed for the treatment of chronic hepatitis B), two other nucleoside analogues, that is, entecavir and L-dT (tel-bivudine) (Fig.4aa), have been licensed for the treatment of HBV infections. Two other compounds 3 -Val-L-dC (valtorcitabine) and L-FMAU (clevudine) (Fig. 4aa) are in clinical development for the treatment of HBV infections, and yet two other compounds, that is, racivir and elvucitabine (Fig. 3), yield potential for the treatment of both HBV and HIV infections. 

Entecavir, telbivudine, clevudine, and the other nucleoside analogues (Fig. 4aa) need to be phosphorylated to their 5 -triphosphate form to be antivirally active (Fig. 8). This again implies three phosphorylation steps based successively on a nucleoside kinase, nucleoside 5 -monophosphate kinase, and nucleoside 5 -diphosphate kinase. These reactions have been characterized only in a few cases, that is, thymidylate kinase in the metabolism of clevudine (Hu et al. 2005). 

In this chapter, we have described the spectrum of antiviral activities that have been discovered beyond the world of nucleoside analogues, protease and fusion inhibitors. The compounds and mechanisms described here may one day add significantly to the armamentarium of antiviral agents, not only against Herpes Simplex, Hepatitis B and Human Immunodeficiency Virus, but also against Hepatitis C and Human Cytomegalovirus. 

Another nucleoside analogue belonging to the same class as lamivudine is tel-bivudine. Clinical resistance to telbivudine has to be studied in more detail, but the first in vivo data and several in vitro results suggest that tebivudine s resistance profile is quite similar to that of lamivudine (Lok et al. 2007). 

Treatment of the allylic sulfoxide 1227 a with diisopropylethylamine (DIPEA) or of 1227 b with N-trimethylsilyldiethylamine 146 and TMSOTf 20 leads in ca. 90% yield to the quaternary amino derivatives 1228 and 1229 and HMDSO 7 [36] (Scheme 8.15). Tetramethylene sulfoxide 1230 reacts with silylated thymine 1231 in the presence of three equivalents of TMSOTf 20 to give the 4 -thio-nucleoside analogue 1232 and HMDSO 7 [37]. Other silylated pyrimidine, pyridine, and purine bases react analogously with cyclic sulfoxides to give 4 -thio-nucleoside analogues [37, 37a, 38]. 

In MeCN/Cl(CH2)2Cl in the presence of SnCU silylated co-hydroxy-acetals such as 1422 react, via cations such as 1423, with silylated 5-fluorouracil 1424 to afford, after aqueous work-up, 84% of the nucleoside analogue 1425 and MeOSiMe3 13 a [7] (Scheme 9.5). 

Cherry CL, Wesselingh SL (2003) Nucleoside analogues and HIV the combined cost to mitochondria. J Antimicrob Chemother 51(5) 1091-1093... 

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