DEVELOPMENT OF PHOSPHORAMIDATE PRONUCLEOTIDE DI-ESTERS
BEARING AN ANCHIMERIC-ASSISTANCE MOIETY
Aniekan Okon, Peter Bitterman, Carston R. Wagner*
Department of Medicinal Chemistry, University of Minnesota
Minneapolis, 55455
Nucleoside analogues are used as therapeutic agents for antiviral and anticancer
interventions. These agents rely on a series of phosphorylation steps to their corresponding 5’
triphosphates, which is ultimately the active metabolite. However, certain drawbacks, chief of
which is the down-regulation of essential kinases of the initial phosphorylation step, reduces the
efficacy of nucleoside analogues as therapeutic agents, which could lead to cellular resistance. A
strategy for overcoming the problem of reduced kinase activity would be to directly deliver
nucleotides in vivo. However, the polar nature of nucleotides makes it highly unlikely that such
direct delivery can be achieved. In order to improve cellular delivery of such a highly polar
compound, pronucleotide strategies have been developed. Phosphoramidate pronucleotides have
been demonstrated to have effective cellular delivery and as a result many laboratories and
pharmaceutical companies have developed phosphoramidate pronucleotide-based compounds. In
particular, we have previously demonstrated the effective cellular delivery of various nucleoside
analogues.
Unfortunately, these phosphoramidate monoesters have poor in vivo bioavailability,
despite good in vitro potency. To overcome this liability, phosphoramidate di-ester
pronucleotides have been developed. These di-esters undergo a series of activation steps to
reveal the desired nucleotide. This work presents our efforts at developing di-ester
pronucleotides bearing an anchimeric-assisting moiety to facilitate conversion to the monoester
intermediate. Such strategy bypasses esterase activation that is common for most di-ester
pronucleotides reported in literature.