Design, synthesis, and preliminary evaluation of doxazolidine carbamates as prodrugs activated by carboxylesterases.

Abstract

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

• Authors: David J Burkhart, Benjamin L Barthel, Glen C Post, Brian T Kalet, Jordan W Nafie, Richard K Shoemaker, Tad H Koch
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 49 Issue 24 Pg. 7002-12 (Nov 30 2006) ISSN: 0022-2623 [Print] United States
• PMID: 17125253 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Carbamates
• Oxazoles
• Prodrugs
• RNA, Messenger
• pentyl 4-(N-doxazolidinylcarbonyloxymethyl)phenylcarbamate
• Doxorubicin
• Carboxylic Ester Hydrolases

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Carbamates (chemical synthesis, chemistry, pharmacology)
• Carboxylic Ester Hydrolases (biosynthesis, metabolism)
• Cell Line
• Cell Line, Tumor
• Doxorubicin (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Drug Design
• Drug Screening Assays, Antitumor
• Humans
• Models, Molecular
• Molecular Conformation
• Myocytes, Cardiac (drug effects)
• Oxazoles (chemical synthesis, chemistry, pharmacology)
• Prodrugs (chemical synthesis, chemistry, pharmacology)
• RNA, Messenger (biosynthesis)
• Rats
• Structure-Activity Relationship