Aryloxy Pivaloyloxymethyl Prodrugs as Nucleoside Monophosphate Prodrugs

Abstract

Intracellular phosphorylation of therapeutic nucleoside analogues into their active triphosphate metabolites is a prerequisite for their pharmacological activity. However, the initial phosphorylation of these unnatural nucleosides into their monophosphate derivatives can be a rate-limiting in their activation. To address this, we herein report the development of the aryloxy pivaloyloxymethyl prodrugs (POMtides) as a novel and effective nucleoside monophosphate prodrug technology and its successful application to the anticancer nucleoside analogue 5-fluoro-2'-deoxyuridine (FdUR).

Prodrugs of a 1-Hydroxy-2-oxopiperidin-3-yl Phosphonate Enolase Inhibitor for the Treatment of ENO1-Deleted Cancers

“…Finally, a cancer-specific prodrug of 5 coupled with a genomically rationalized target would further widen the therapeutic window between cancer and normal cells: this could open the possibility of targeting ENO1- heterozygous - deleted cancers, which comprise a larger patient population. During our screening, we also identified several novel promoieties with distinct mechanisms of bioactivation from reported phosph­(on)­ate prodrug strategies (e.g., Farquhar, McGuigan/ProTide, and HepDirect), which may be of interest to those in the phosph­(on)­ate prodrug field. ,− Here, we describe the in vitro activity of some novel prodrugs of 5 for the treatment of glycolysis-deficient cancers.…”

“…During our screening, we also identified several novel promoieties with distinct mechanisms of bioactivation from reported phosph(on)ate prodrug strategies (e.g., Farquhar, McGuigan/ProTide, and HepDirect), which may be of interest to those in the phosph(on)ate prodrug field. 18 , 22 − 24 Here, we describe the in vitro activity of some novel prodrugs of 5 for the treatment of glycolysis-deficient cancers.…”

Anticancer Effect of Chlorambucil Enhanced by Chiral Phthalidyl Promoiety

“…Prodrug is a forceful strategy to enhance the biopharmaceutical profiles of drugs. [1][2][3][4][5][6][7] It's structurally comprised of a promoiety unit and a parent drug unit. In past decades, prodrugs have advanced from an old drug discovery strategy to the intentionally designed technique, since it can economically address the pharmacodynamic and pharmacokinetic drawbacks during drug development.…”

“…Prodrug is a forceful strategy to enhance the biopharmaceutical profiles of drugs [1–7] . It's structurally comprised of a promoiety unit and a parent drug unit.…”

Peroxide-Mediated Release of Organophosphates from Boron-Containing Phosphotriesters: A New Class of Organophosphate Prodrugs

“…Phosphodiesters that contain an aryl and an alkyl group cleave selectively as shown in the conversion of 16 to 17 . Aryl phosphates can be cleaved enzymatically to release monoalkyl phosphates . Compound 18 , in which the BPin group is replaced by the recently reported and more easily handled EPin group, releases 9 extremely efficiently, albeit somewhat more slowly.…”