Four novel potential prodrugs derived from daunorubicin (8, 10) and doxorub
icin (12, 14) were designed and synthesized. They are self-immolative prodr
ugs for suicide gene therapy activation by the enzyme carboxypeptidase G2 (
CPG2) subsequently releasing the corresponding anthracyclines, by a 1,6-eli
mination mechanism. A mammary carcinoma cell line (MDA MB 361) was engineer
ed to express CPG2 intracellularly (CPG2*) or extracellularly, tethered to
the outer cell membrane (stCPG2(Q)3). The prodrugs derived from doxorubicin
showed prodrug/drug cytotoxicity differentials of 21-fold (compound 12) an
d 23-fold (compound 14). Prodrug 12 underwent an 11-fold activation when as
sayed in the cell line expressing externally surface-tethered CPG2.