P-stereocontrolled synthesis of oligo(nucleoside N3'→O5' phosphoramidothioate)s - opportunities and limitations.

3'--(2-Thio-1,3,2-oxathiaphospholane) derivatives of 5'--DMT-3'-amino-2',3'-dideoxy-ribonucleosides (OTP-N), that bear a 4,4-unsubstituted, 4,4-dimethyl, or 4,4-pentamethylene substituted oxathiaphospholane ring, were synthesized. Within these three series, OTP-N differed by canonical nucleobases (, Ade, Cyt, Gua, or Thy). The monomers were chromatographically separated into P-diastereomers, which were further used to prepare NN' dinucleotides (3), as well as short P-stereodefined oligo(deoxyribonucleoside N3'→O5' phosphoramidothioate)s (NPS-) and chimeric NPS/PO- and NPS/PS-oligomers.

Synthesis of PS/PO-chimeric oligonucleotides using mixed oxathiaphospholane and phosphoramidite chemistry.

Chimeric oligonucleotides containing phosphodiester and phosphorothioate linkages have been obtained using the solid phase synthesis. The oligonucleotide parts possessing natural internucleotide phosphate bonds were assembled using commercially available nucleoside 3'-O-(2-cyanoethyl-N,N-diisopropylamino)phosphoramidites 7 whereas the phosphorothioate segment was built using nucleoside 3'-O-(2-thio-1,3,2-oxathiaphospholanes) 3. The oxidation steps, crucial for the conversion of phosphite linkages into the phosphate moieties, were conducted using tert-butylperoxy-trimethylsilane, and this reagent was not harmful to the diester phosphorothioate linkages.

N-Acyl-phosphoramidates as potential novel form of gemcitabine prodrugs.

Gemcitabine (dFdC) is a cytidine analog remarkably active against a wide range of solid tumors. Inside a cell, gemcitabine is phosphorylated by deoxycytidine kinase to yield gemcitabine monophosphate, further converted to gemcitabine di- and triphosphate. The most frequent form of acquired resistance to gemcitabine in vitro is the deoxycytidine kinase deficiency.

Synthesis and an antiviral activity evaluation of nucleoside 5´-O-(N-acyl) phosphoramidates.

Background: pyrimidine nucleoside analogues represent an established class of clinically useful antiviral agents. Once inside the cell, they are activated by a series of intracellular phosphorylation steps to produce 5´-triphosphate derivatives. In many cases, nucleoside analogues are poor substrates for the cellular kinases needed for their activation.