Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 30, Issue 11, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2020.127148
Keywords
Prostate specific antigen; Disulfiram; Diethyldithiocarbamate; Prochelator; Copper
Categories
Funding
- Duke Cancer Institute P30 Cancer Center Support Grant [NIH CA014236]
- Royal Government of Thailand`s Development and Promotion of Science and Technology Talents Project
- FoersterBernstein Postdoctoral Fellowship
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Disulfiram in conjunction with copper has been shown to be a potent anticancer agent. However, disulfiram's therapeutic potential in prostate cancer is hindered by off-target effects due to its reactive and nucleophilic thiol-containing component, diethyldithiocarbamate (DTC). To minimize undesirable reactivity, we have strategically blocked the thiol moiety in DTC with a cleavable p-aminobenzyl (pAB) group linked to peptide substrates recognized by prostate specific antigen (PSA). Here we report the synthesis and evaluation in cancer cell models of two PSA-activatable prodrugs: HPD (Ac-HSSKLQL-pAB-DTC and RPD (RSSYYSL-pAB-DTC). In vitro exposure to PSA was found to trigger activation of HPD and RPD to release diethyldithiocarbamate, and both prodrugs were found to induce toxicity in prostate cancer cells, with HPD showing the most promising selectivity. With copper supplementation, the IC50 of HPD was 1.4 mu M in PSA-expressing LNCaP cells, and 11 mu M in PC3 cells that do not express PSA. These studies demonstrate the utility of using peptide recognition handles to direct the activity of dithiocarbamate prodrugs for selective cytotoxicity of cancer cells.
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