Synthetic nucleosides and nucleotides. XXI. On the synthesis and biological evaluations of 2'-deoxy-.ALPHA.-D-ribofuranosyl nucleosides and nucleotides.

Abstract

N4-Benzoyl-2''-deoxycytidine was converted to its 3'',5''-di-O-acetate (2). Compound 2 was smoothly anomerized to its .alpha.-counterpart (3) by reaction with trimethylsilyl trifluoromethanesulfonate (TMS-triflate). Saponification of 3 afforded crystalline .alpha.-2''-deoxycytidine (4). Similarly, 3'',5''-di-O-p-toluoyl-2''-deoxythymidine was anomerized to the .alpha.-anomer, which was then deblocked to give .alpha.-2''-deoxythymidine. .alpha.-2''-Deoxyadenosine and 9-(2-deoxy-.alpha.-D-ribofuranosyl)-6-methylthiopurine were prepared by TMS-triflate-catalyzed trans-2-deoxyribosylation from 2 to N6-benzoyladenine and 6-methylthiopurine, respectively. .alpha.-5''-Fluoro-2''-deoxycytidine (11a) and its .beta.-anomer were synthesized by the reaction of the trimethylsilyl derivative of N4-p-toluoyl-5-fluoroxytosine with 1-O-acetyl-3,5-di-O-benzoyl-2-deoxy-D-ribofuranose followed by deblocking. Among the compounds related to .alpha.-2''-deoxyribonucleosides, 4 and 11a showed weak growth-inhibitory activity against mouse leukemia L5178Y cells in culture. Of the nucleoside 5''-triphosphates, .alpha.-deoxy ATP had some affinity with DNA polymerase .alpha. when activated DNA was used as a template-primer. .alpha.-Deoxy TTP showed a remarkable inhibitory effect on DNA polymerase .beta. when poly [rA]-oligo[dT] was used as template-primer.