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Dithiocarbamate prodrugs activated by prostate specific antigen to target prostate cancer.

Publication ,  Journal Article
Bakthavatsalam, S; Wiangnak, P; George, DJ; Zhang, T; Franz, KJ
Published in: Bioorg Med Chem Lett
June 1, 2020

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.

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Published In

Bioorg Med Chem Lett

DOI

EISSN

1464-3405

Publication Date

June 1, 2020

Volume

30

Issue

11

Start / End Page

127148

Location

England

Related Subject Headings

  • Thiocarbamates
  • Prostatic Neoplasms
  • Prostate-Specific Antigen
  • Prodrugs
  • Medicinal & Biomolecular Chemistry
  • Male
  • Humans
  • Copper
  • Cell Survival
  • Cell Line, Tumor
 

Citation

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Bakthavatsalam, S., Wiangnak, P., George, D. J., Zhang, T., & Franz, K. J. (2020). Dithiocarbamate prodrugs activated by prostate specific antigen to target prostate cancer. Bioorg Med Chem Lett, 30(11), 127148. https://doi.org/10.1016/j.bmcl.2020.127148
Bakthavatsalam, Subha, Petpailin Wiangnak, Daniel J. George, Tian Zhang, and Katherine J. Franz. “Dithiocarbamate prodrugs activated by prostate specific antigen to target prostate cancer.Bioorg Med Chem Lett 30, no. 11 (June 1, 2020): 127148. https://doi.org/10.1016/j.bmcl.2020.127148.
Bakthavatsalam S, Wiangnak P, George DJ, Zhang T, Franz KJ. Dithiocarbamate prodrugs activated by prostate specific antigen to target prostate cancer. Bioorg Med Chem Lett. 2020 Jun 1;30(11):127148.
Bakthavatsalam, Subha, et al. “Dithiocarbamate prodrugs activated by prostate specific antigen to target prostate cancer.Bioorg Med Chem Lett, vol. 30, no. 11, June 2020, p. 127148. Pubmed, doi:10.1016/j.bmcl.2020.127148.
Bakthavatsalam S, Wiangnak P, George DJ, Zhang T, Franz KJ. Dithiocarbamate prodrugs activated by prostate specific antigen to target prostate cancer. Bioorg Med Chem Lett. 2020 Jun 1;30(11):127148.
Journal cover image

Published In

Bioorg Med Chem Lett

DOI

EISSN

1464-3405

Publication Date

June 1, 2020

Volume

30

Issue

11

Start / End Page

127148

Location

England

Related Subject Headings

  • Thiocarbamates
  • Prostatic Neoplasms
  • Prostate-Specific Antigen
  • Prodrugs
  • Medicinal & Biomolecular Chemistry
  • Male
  • Humans
  • Copper
  • Cell Survival
  • Cell Line, Tumor