Synthesis and Biological Characterization of Protease-Activated Prodrugs of Doxazolidine
| Autor: | Sean M. Colvin, Daniel L. Rudnicki, David J. Burkhart, Benjamin L. Barthel, Tad H. Koch, Thomas Price Kirby |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Proteases
Plasmin medicine.medical_treatment Antineoplastic Agents Chemistry Techniques Synthetic Article Cathepsin B Phosphates Drug Stability Cell Line Tumor Drug Discovery medicine Humans Doxorubicin Oxazoles Cell Proliferation Protease Chemistry Prodrug Trypsin Kinetics Biochemistry Proteolysis Cancer cell Molecular Medicine Peptide Hydrolases medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 55:6595-6607 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Doxazolidine (doxaz) is a new anthracycline anticancer agent. While structurally similar to doxorubicin (dox), doxaz acts via a distinct mechanism to selectively enhance anticancer activity over cardiotoxicity, the most significant clinical impediment to successful anthracycline treatment. Here, we describe the synthesis and characterization of a prodrug platform designed for doxaz release mediated by secreted proteolytic activity, a common association with invasiveness and poor prognosis in cancer patients. GaFK-Doxaz is hydrolyzable by the proteases plasmin and cathepsin B, both strongly linked with cancer progression, as well as trypsin. We demonstrate that activation of GaFK-Doxaz releases highly potent doxaz that powerfully inhibits the growth of a wide variety of cancer cells (average IC(50) of 8 nM). GaFK-Doxaz is stable in human plasma and is poorly membrane permeable, thereby limiting activation to locally secreted proteolytic activity and reducing the likelihood of severe side effects. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|