Anchimerically Activated ProTides as Inhibitors of Cap-Dependent Translation and Inducers of Chemosensitization in Mantle Cell Lymphoma

The cellular delivery of nucleotides
through various pronucleotide
strategies has expanded the utility of nucleosides as a therapeutic
class. Although highly successful, the highly popular ProTide system
relies on a four-step enzymatic and chemical process to liberate the
corresponding monophosphate. To broaden the scope and reduce the number
of steps required for monophosphate release, we have developed a strategy
that depends on initial chemical activation by a sulfur atom of a
methylthioalkyl protecting group, followed by enzymatic hydrolysis
of the resulting phosphoramidate monoester. We have employed this
ProTide strategy for intracellular delivery of a nucleotide antagonist
of eIF4E in mantle cell lymphoma (MCL) cells. Furthermore, we demonstrated
that chemical inhibition of cap-dependent translation results in suppression
of c-Myc expression, increased p27 expression, and enhanced chemosensitization
to doxorubicin, dexamethasone, and ibrutinib. In addition, the new
ProTide strategy was shown to enhance oral bioavailability of the
corresponding monoester phosphoramidate.