Dithiocarbamate prodrugs activated by prostate specific antigen to target prostate cancer

Subha Bakthavatsalam, Petpailin Wiangnak, Daniel J. George, Tian Zhang, Katherine J. Franz

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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 µM in PSA-expressing LNCaP cells, and 11 µM 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.

Original languageEnglish (US)
Article number127148
JournalBioorganic and Medicinal Chemistry Letters
Volume30
Issue number11
DOIs
StatePublished - Jun 1 2020
Externally publishedYes

Keywords

  • Copper
  • Diethyldithiocarbamate
  • Disulfiram
  • Prochelator
  • Prostate specific antigen

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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