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Synthesis and biological characterization of protease-activated prodrugs of doxazolidine.

Abstract
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.
AuthorsBenjamin L Barthel, Daniel L Rudnicki, Thomas Price Kirby, Sean M Colvin, David J Burkhart, Tad H Koch
JournalJournal of medicinal chemistry (J Med Chem) Vol. 55 Issue 14 Pg. 6595-607 (Jul 26 2012) ISSN: 1520-4804 [Electronic] United States
PMID22742660 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Oxazoles
  • Phosphates
  • doxazolidine
  • Doxorubicin
  • Peptide Hydrolases
Topics
  • Antineoplastic Agents (blood, chemistry, metabolism, pharmacology)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Chemistry Techniques, Synthetic
  • Doxorubicin (analogs & derivatives, blood, chemical synthesis, chemistry, metabolism, pharmacology)
  • Drug Stability
  • Humans
  • Kinetics
  • Oxazoles (blood, chemical synthesis, chemistry, metabolism, pharmacology)
  • Peptide Hydrolases (metabolism)
  • Phosphates (chemistry)
  • Proteolysis

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