5 Alkylpyrimidine nucleosides. Preparation and properties of 5 ethyl 2' deoxycytidine and related nucleosides

Article abstract of DOI:10.1021/jm00249a003

The α and β anomers of 5 ethyl 2' deoxycytidine were prepared by thiation and amination of the known α,β 3',5' di O (p chlorobenzoyl) 5 ethyl 2' deoxyuridine and by condensation of O²,N⁴ bis(trimethylsilyl) 5 ethylcytosine with 2 deoxy 3,5 di O (p toluoyl) D erythro pentofuranosyl chloride. The former procedure simultaneously makes available the 4 thiothymidine analogs, α and β 5 ethyl 4 thio 2 deoxyuridines, while the latter provides an alternative route to the known antiviral thymidine analog, 5 ethyl 2' deoxyuridine. Minor improvements were introduced in the thiation procedure. Furthermore, the relative mobilities on silica gel of the α and β anomers of the blocked thiated nucleosides differed sufficiently to permit their preparative separation by tlc with only a single development; the possible general applicability of this fact to fractionation of anomeric nucleosides is emphasized. Circular dichroism data for all the anomeric nucleoside pairs are reported. The β anomer of 5 ethyl 2' deoxycytidine exhibited low, but significant, activity against herpes simplex virus, but not vaccinia or vesicular stomatitis viruses, in primary rabbit kidney cell cultures. In combination with 5 fluorouracil, β 5 ethyl 2 2' deoxycytidine provoked additional reversible growth inhibition in Salmonella typhimurium following its in vivo deamination to 5 ethyl 2' deoxyuridine. The α and β anomers of 5 ethyl 2' deoxycytidine 5 phosphate were prepared by standard phosphorylation procedures; the α anomer was dephosphorylated by snake venom 5 nucleotidase at a rate comparable to that for the β anomer, a result of some interest in relation to the specificity of 5 nucleotidase.