Isopentenyl pyrophosphate (
IPP) and dimethylallyl
pyrophosphate (
DMAPP) are the central five-
carbon precursors to all
terpenes. Despite their significance, exogenous, independent delivery of
IPP and
DMAPP to cells is impossible as the negatively charged
pyrophosphate makes these molecules membrane impermeant. Herein, we demonstrate a facile method to circumvent this challenge through esterification of the β-
phosphate with two self-immolative
esters (SIEs) that neutralize the negatively charged
pyrophosphate to yield membrane-permeant analogs of
IPP and
DMAPP. Following cellular incorporation, general
esterase activity initiates cleavage of the SIEs, resulting in traceless release of
IPP and
DMAPP for metabolic utilization. Addition of the synthesized
IPP and
DMAPP precursor analogs rescued cell growth of
glioblastoma (U-87MG)
cancer cells concurrently treated with the
HMG-CoA reductase inhibitor pitavastatin, which otherwise abrogates cell growth via blocking production of
IPP and
DMAPP. This work demonstrates a new application of a
prodrug strategy to incorporate a metabolic intermediate and promises to enable future interrogation of the distinct
biological roles of
IPP and
DMAPP.