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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.

SUBMITTER: Barthel BL 

PROVIDER: S-EPMC3433255 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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

Barthel Benjamin L BL   Rudnicki Daniel L DL   Kirby Thomas Price TP   Colvin Sean M SM   Burkhart David J DJ   Koch Tad H TH  

Journal of medicinal chemistry 20120717 14


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 can  ...[more]

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