Fluorescence-guided cancer surgery can dramatically improve
recurrence
rates and postoperative quality of life of patients by accurately
distinguishing the boundary between normal and cancer tissues during
surgery, thereby minimizing excision of normal tissue. One promising
target in early stage cancer is fragile histidine triad (FHIT), a
cancer suppressor protein with dinucleoside triphosphate hydrolase
activity. In this study, we have developed fluorescence probes containing
a nucleoside diphosphate moiety, which dramatically improves the reactivity
and specificity for FHIT, and a moderately lipophilic ester moiety
to increase the membrane permeability. The ester moiety is cleaved
by ubiquitous intracellular esterases, and then, FHIT in the cells
specifically cleaves nucleoside monophosphate. The remaining phosphate
moiety is rapidly cleaved by ubiquitous intracellular phosphatases
to release the fluorescent dye. We confirmed that this probe can detect
FHIT activity in living cells. A comprehensive evaluation of the effects
of various ester moieties revealed that probes with CLogP = 5–7
showed good membrane permeability and were good substrates of the
target enzyme; these findings may be helpful in the rational design
of other multiple phosphate-containing probes targeting intracellular
enzymes.
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