Puromycin Prodrug Activation by Thioredoxin Reductase Overcomes Its Promiscuous Cytotoxicity

Overexpression of the selenoprotein thioredoxin reductase
(TrxR)
has been documented in malignant tissues and is of pathological significance
for many types of tumors. The antibiotic puromycin (Puro) is a protein
synthesis inhibitor causing premature polypeptide chain termination
during translation. The well-defined action mechanism of Puro makes
it a useful tool in biomedical studies. However, the nonselective
cytotoxicity of Puro limits its therapeutic applications. We report
herein the construction and evaluation of two Puro prodrugs, that
is, S1-Puro with a five-membered cyclic disulfide trigger and S2-Puro
with a linear disulfide trigger. S1-Puro is selectively activated
by TrxR and shows the TrxR-dependent cytotoxicity to cancer cells,
while S2-Puro is readily activated by thiols. Furthermore, S1-Puro
displays higher stability in plasma than S2-Puro. We expect that this
prodrug strategy may promote the further development of Puro as a
therapeutic agent.