NOVEL ACYCLIC NUCLEOTIDES AND NUCLEOSIDE 5'-TRIPHOSPHATES IMITATING 2',3'-DIDEOXY-2',3'-DIDEHYDRONUCLEOTIDES - SYNTHESIS AND BIOLOGICAL PROPERTIES

A series of pyrophosphoryl (Z)-(phosphonomethoxy)but-2-enyl derivative s of pyrimidines and purines 9a-d and the corresponding phosphonates 1 0a-d were synthesized. The prepared compounds contain the phosphonate group as an a-phosphate mimic as well as an acyclic residue emulating the sugar moiety in 2',3'-dideoxy-2',3 '-didehydronucleoside 5'-tripho sphates known as highly potent chain terminators of DNA polymerases. P hosphonates 10a-d were obtained by alternative alkylations of the nucl eic bases followed by condensation with ethyl [[(p-tolylsulfonyl)oxy]m ethyl]phosphonate. Pyrophosphorylation of 10a-d afforded phosphonate d iphosphates 9a-d. Their substrate properties were evaluated in cell-fr ee systems containing various DNA polymerases including viral reverse transcriptases. Compounds 9a-d manifested good terminating substrate p roperties toward HTV-1 and AMV reverse transcriptases. They exhibited high selectivity and were not recognized by human DNA polymerases a an d epsilon, DNA polymerase beta from rat liver, Escherichia coli DNA po lymerase I, and HSV-1 and CMV DNA polymerases. Phosphonates 10b-d disp layed no activity in HIV-1-infected MT-4 cells cultures; 10a was moder ately effective (ED(50) = 9 mu M).