| Abstract
| - The synthesis and tumor cell growth inhibition by doxazolidine carbamate prodrugs are reported. Thecarbamates were designed for selective hydrolysis by one or more human carboxylesterases to releasedoxazolidine (Doxaz), the formaldehyde−oxazolidine of doxorubicin that cross-links DNA to trigger celldeath. Simple butyl and pentyl, but not ethyl, carbamate prodrugs inhibited the growth of cancer cells thatoverexpress carboxylesterase CES1 (hCE1) and CES2 (hiCE). Relative CES1 and CES2 expression levelswere determined by reverse transcription of the respective mRNAs, followed by polymerase chain reactionamplification. More complex structures with a p-aminobenzyl alcohol (PABA) self-eliminating spacer showedbetter growth inhibition (IC50 = 50 nM for Hep G2 liver cancer cells) while exhibiting reduced toxicitytoward rat cardiomyocytes, relative to the parent drug doxorubicin. Pentyl 4-(N-doxazolidinylcarbonyloxymethyl)phenylcarbamate, the lead compound for further investigation, appears to be activated in HepG2 cells that express both CES1 and CES2.
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