220503-64-0Relevant academic research and scientific papers
Aspartic acid based nucleoside phosphoramidate prodrugs as potent inhibitors of hepatitis C virus replication
Maiti, Munmun,Maiti, Mohitosh,Rozenski, Jef,De Jonghe, Steven,Herdewijn, Piet
, p. 5158 - 5174 (2015/05/13)
In view of a persistent threat to mankind, the development of nucleotide-based prodrugs against hepatitis C virus (HCV) is considered as a constant effort in many medicinal chemistry groups. In an attempt to identify novel nucleoside phosphoramidate analogues for improving the anti-HCV activity, we have explored, for the first time, aspartic acid (Asp) and iminodiacetic acid (IDA) esters as amidate counterparts by considering three 2′-C-methyl containing nucleosides, 2′-C-Me-cytidine, 2′-C-Me-uridine and 2′-C-Me-2′-fluoro-uridine. Synthesis of these analogues required protection for the vicinal diol functionality of the sugar moiety and the amino group of the cytidine nucleoside to regioselectively perform phosphorylation reaction at the 5′-hydroxyl group. Anti-HCV data demonstrate that the Asp-based phosphoramidates are ～550 fold more potent than the parent nucleosides. The inhibitory activity of the Asp-ProTides was higher than the Ala-ProTides, suggesting that Asp would be a potential amino acid candidate to be considered for developing novel antiviral prodrugs.
2'-C-branched ribonucleosides: Synthesis of the phosphoramidite derivatives of 2'-C-β-methylcytidine and their incorporation into oligonucleotides
Tang, Xiao-Qing,Liao, Xiangmin,Piccirilli, Joseph A.
, p. 747 - 754 (2007/10/03)
We describe a strategy for the incorporation of a 2'-C-branched ribonucleoside, 2'-C-β-methylcytidine, into oligonucleotides via solid- phase synthesis using phosphoramidite derivatives. 4-N-Benzoyl-2'-C-β- methylcytidine (2b) was synthesized by coupling persilylated 4-N- benzoylcytosine with 1,2,3,5-tetra-O-benzoyl-2-C-β-methyl-α-(and β)-D- ribofuranose (1) in the presence of SnCl4 in acetonitrile, followed by selective deprotection with NaOH in pyridine/methanol. The 3'- and 5'- hydroxyl groups were blocked as a cyclic di-tert-butylsilanediyl ether 3 by treatment with di-tert-butyldichlorosilane/AgNO3 in DMF. The 2'-hydroxyl group was then protected as a tert-butyldimethylsilyl ether 4a by treatment with tert-butylmagnesium chloride followed by addition of tert- butyldimethylsilyl trifluoromethanesulfonate in THF. As an alternative to 2'- silyl protection, the corresponding 2'O-tetrahydropyranyl ether 4b was prepared by treatment of 3 with 4,5-dihydro-2H-pyran in the presence of a catalytic amount of 10-camphorsulfonic acid in methylene chloride. The di- tert-butylsilanediyl groups of 4a and 4b were removed by treatment with pyridinium poly(hydrogen fluoride) to afford 5a and 5b, respectively. Protection of the 5'-hydroxyl group as a dimethoxytrityl ether and phosphitylation of the 3'-hydroxyl group by the standard procedure gave the phosphoramidite derivatives 7a and 7b. Both 7a and 7b could be used to incorporate 2'-C-β-methylcytidine into oligonucleotides efficiently via standard solid-phase synthesis, but the tetrahydropyranyl group of 7b was more readily removed from oligonucleotides than the tert-butyldimethylsilyl group of 7a. Oligonucleotides containing 2'-C-β-methylcytidine undergo base- catalyzed degradation analogous to natural RNA.
