PRODRUGS OF OLIGONUCLEOTIDES - THE ACYLOXYALKYL ESTERS OF OLIGODEOXYRIBONUCLEOSIDE PHOSPHOROTHIOATES

In model studies toward development of prodrugs of oligonucleoside pho sphorothioates, R(p) and S-p, S-alkyl phosphorothiolates 3a-d were pre pared by chemoselective S-alkylation of R(p) acid S-p dinucleoside pho sphorothioate 2 with iodoalkyl acylates 9a-d. When incubated with huma n serum or porcine liver esterase (PLE), stereospecific conversion of 3a-d to R(p) and S(p)2 was observed. Stereodifferentiation was also no ted in the hydrolysis-S-p faster than R(p) 3a-c, with serum, and R(p) faster than S(p)3a-c, with PLE. In the case of hindered analogs 3c, de sulfurized product 4 was also formed along with 2. Mechanisms to accou nt for this product profile obtained during the hydrolysis are propose d. Similarly, bioreversion of acyloxyalkyl oligonucleoside phosphoroth ioates 15, 16, and 17 to 18, 19, and 20, respectively,was demonstrated by P-31 NMR and PAGE. (C) 1995 Academic Press, Inc.