DEVELOPMENT OF CELL PERMEANT INHIBITORS OF TYPE 1 HUMAN ISOPENTENYL DIPHOSPHATE ISOMERASE

Isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) are the 5C precursors to all isoprenoids. Isoprenoid biosynthesis occurs via a head-to-tail condensation of the initiator, DMAPP, and extender unit, IPP which demonstrates high metabolic demand. However, the reversible isomerization catalyzed by type 1 isopentenyl diphosphate isomerase indicates a preference towards DMAPP synthesis, which combined with the limited evidence available of the independent functions of the 5C precursors in humans, underscores the requirement for interrogation of their distinct biological roles that occur to maintain homeostasis. We sought to modulate the metabolic flux of IPP and DMAPP by the inhibition of hIDI-1 which allows their isolation for independent investigations. Inhibitors of IDI-1 reported in the literature are pyrophosphates and the resulting cell impermeability limits the application in human systems. Herein, we demonstrate the application of self-immolative esters (SIE) as a prodrug approach to selectively mask the negative charges on the beta-phosphate of substrate analogs for the synthesis of a series of cell-permeant inhibitors of hIDI-1. The inhibitory potential of inhibitors 1-3 have been evaluated in vitro and inhibitors 1 and 2 have been subjected to further analysis on MDA-MB-231 breast cancer cells. The inhibitory efficiency of the reported analogs follows the trend 1>2>3. In the present study, we also investigated the photo uncaging efficiency of a mixed photocaged IPP compound, that employs an SIE to induce lipophilicity for exogenous delivery of IPP into the cell, and an ortho-nitrobenzyl (oNB) photocage, that utilizes light as an external stimulus for the non-invasive spatiotemporal control over the release of IPP.