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.
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Authors | Benjamin L Barthel, Daniel L Rudnicki, Thomas Price Kirby, Sean M Colvin, David J Burkhart, Tad H Koch |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 55
Issue 14
Pg. 6595-607
(Jul 26 2012)
ISSN: 1520-4804 [Electronic] United States |
PMID | 22742660
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- Oxazoles
- Phosphates
- doxazolidine
- Doxorubicin
- Peptide Hydrolases
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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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