Prodrugs of Oligonucleotides: The Acyloxyalkyl Esters of Oligodeoxyribonucleoside Phosphorothioates

✍ Scribed by R.P. Iyer; D. Yu; S. Agrawal

• Publisher: Elsevier Science
• Year: 1995
• Tongue: English
• Weight: 933 KB
• Volume: 23
• Category: Article
• ISSN: 0045-2068
• DOI: 10.1006/bioo.1995.1001

✦ Synopsis

In model studies toward development of prodrugs of oligonucleoside phosphorothioates, (R_{\mathrm{p}}) and (S_{\mathrm{p}}, S)-alkyl phosphorothiolates 3a-d were prepared by chemoselective S-alkylation of (R_{\mathrm{p}}) and (S_{\mathrm{p}}) dinucleoside phosphorothioate 2 with iodoalkyl acylates 9a-d. When incubated with human serum or porcine liver esterase (PLE), stereospecific conversion of 3a-d to (R_{\mathrm{P}}) and (S_{p} 2) was observed. Stereodifferentiation was also noted in the hydrolysis (-S_{p}) faster than (R_{\mathrm{p}}) 3a-c, with serum, and (R_{\mathrm{p}}) faster than (S_{\mathrm{p}} \mathbf{3 a - c}), with PLE. In the case of hindered analogs (3 \mathbf{3}), desulfurized product (\mathbf{4}) was also formed along with 2 . Mechanisms to account for this product profile obtained during the hydrolysis are proposed. Similarly, bioreversion of acyloxyalkyl oligonucleoside phosphorothioates 15,16 , and 17 to 18,19 , and 20 , respectively, was demonstrated by ({ }^{3 /}) P NMR and PAGE. 1999 Academic Press. Inc.