title: 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.
authors: Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309-0215, USA.
authors: Benjamin L
authors: BL
authors: Barthel
authors: Daniel L
authors: DL
authors: Rudnicki
authors: Thomas Price
authors: TP
authors: Kirby
authors: Sean M
authors: SM
authors: Colvin
authors: David J
authors: DJ
authors: Burkhart
authors: Tad H
authors: TH
authors: Koch
mesh_terms: D000970:Antineoplastic Agents / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004355:Drug Stability; D006801:Humans; D007700:Kinetics; D010080:Oxazoles / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D010447:Peptide Hydrolases / Q000378:metabolism*; D010710:Phosphates / Q000737:chemistry; D059748:Proteolysis
chemical_list: D000970:Antineoplastic Agents; D010080:Oxazoles; D010710:Phosphates; C545998:doxazolidine; D004317:Doxorubicin; D010447:Peptide Hydrolases