We previously reported the
application of the aryloxy triester phosphoramidate prodrug technology to the
phosphoantigen (E)-4-hydroxybut-2-enyl phosphate (HMBP). Although these prodrugs
exhibited potent activation of Vγ9/Vδ2 T‐cell immune responses, their stability
was low due to the rapid cleavage of the -O-P- bond. To address this, we herein
report the application of the same prodrug strategy to two HMBP phosphonates,
which have stable -CH2-P- or -CF2-P- bonds. These HMBP phosphonate prodrugs,
phosphonamidates, exhibited excellent serum stability and potent activation of
Vgama9/Vdelta2 T‐cells making them attractive compounds for further development as
potential immunotherapeutics.
