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 PCR amplification. More complex structures with a p-aminobenzyl alcohol (PABA) self-eliminating spacer showed better growth inhibition (IC 50 50 nM for Hep G2 liver cancer cells) while exhibiting reduced toxicity toward rat cardiomyocytes, relative to the parent drug doxorubicin. Pentyl 4-(Ndoxazolidinylcarbonyloxymethyl) phenylcarbamate (pentyl PABC-Doxaz) the lead compound for further investigation, appears to be activated in Hep G2 cells that express both CES1 and CES2.

Anticancer prodrugs of butyric acid and formaldehyde protect against doxorubicin-induced cardiotoxicity

“…Taken together, it can be deduced that protection concurs with increased cellular formaldehyde. Along the same line, Burkhart et al (2006) have shown that a Dox-formaldehyde conjugate inhibited the growth of cancer cells better than that of cardiomyocytes while Dox displayed the opposite specificity.…”

Doxazolidine Induction of Apoptosis by a Topoisomerase II Independent Mechanism

“…43 An example of a hydrolytically stable, nontoxic doxazolidine conjugate targeted to cancer cells that overexpress a carboxylesterase enzyme was recently reported. 43 Other enzymes currently being evaluated for activation of doxazolidine prodrugs at the site of tumors are plasmin and carboxypeptidase G2. Plasmin is of particular interest because of its role in metastatic tumor cell invasion of new tissue and subsequent tumor angiogenesis.…”

Synthesis and antiproliferative activities against Hep-G2 of salicylanide derivatives: potent inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase

“…Salicylanilides are usually synthesised from substituted salicylic acids and anilines. Salicylanilide derivatives isolated from natural plants have been reported to possess antiproliferative activities against the Hep-G2 cell line, a type of liver cancer cell often selected for research to test compounds that may possess potent activity for liver cancer treatment [1][2][3]. Pei-Wen Hsieh et al reported the isolation of 4-methoxydianthramide B, a salicylanilide derivative, from the traditional Chinese medicinal plant Dianthus superbus.…”