(E)-4-Hydroxy-3-methyl-but-2-enyl diphosphate (1, HMBPP) is an intermediate in bacterial biosynthesis of isoprenoids, and can be viewed as the final stage before the non-mevalonate pathway merges with the pathway for isoprenoid biosynthesis found in mammals. This compound activates a subset of human T cells known as γδ T-cells, and because of this activity it has been described as a phosphoantigen. This compound is believed to function through binding to the protein butyrophilin 3A1 although a detailed mechanism of action is as yet elusive. Closely related phosphonates (2) also can serve as agonists of this protein, and may be able to stimulate an immune response that would be useful for treatment of infections or malignancies. We recently have reported that derivatives of compound 2 which can be viewed as prodrugs (e.g. 3 and 4) demonstrate dramatically increased potency vis-à-vis the parent phosphonate, presumably because they enhance cellular uptake. We have prepared a number of additional variations on these structures and determined their ability to stimulate γδ T-cells. The details of these syntheses and the biological activity of the new analogues will be presented.

Synthesis and biological activity of hydroxymethylbutenyl diphosphate mimics for T-cell activation

250th National Meeting (2015)

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