Missing Selectivity of Targeted 4 beta-Phorbol Prodrugs Expected to be Potential Chemotherapeutics

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Tarvainen , I , Zimmermann , T , Heinonen , P , Jäntti , M H , Yli-Kauhaluoma , J , Talman , V , Franzyk , H , Tuominen , R K & Christensen , S B 2020 , ' Missing Selectivity of Targeted 4 beta-Phorbol Prodrugs Expected to be Potential Chemotherapeutics ' , ACS Medicinal Chemistry Letters , vol. 11 , no. 5 , pp. 671-677 . https://doi.org/10.1021/acsmedchemlett.9b00554 , https://doi.org/10.1021/acsmedchemlett.9b00554

Title: Missing Selectivity of Targeted 4 beta-Phorbol Prodrugs Expected to be Potential Chemotherapeutics
Author: Tarvainen, Ilari; Zimmermann, Tomas; Heinonen, Pia; Jäntti, Maria Helena; Yli-Kauhaluoma, Jari; Talman, Virpi; Franzyk, Henrik; Tuominen, Raimo K.; Christensen, Søren Brøgger
Contributor: University of Helsinki, Division of Pharmacology and Pharmacotherapy
University of Helsinki, Division of Pharmacology and Pharmacotherapy
University of Helsinki, PREP in neurodegenerative disorders
University of Helsinki, Division of Pharmaceutical Chemistry and Technology
University of Helsinki, Drug Research Program
University of Helsinki, Division of Pharmacology and Pharmacotherapy
Date: 2020-05-14
Language: eng
Number of pages: 7
Belongs to series: ACS Medicinal Chemistry Letters
ISSN: 1948-5875
URI: http://hdl.handle.net/10138/323623
Abstract: Targeting cytotoxic 4 beta-phorbol esters toward cancer tissue was attempted by conjugating a 4 beta-pborbol derivative with substrates for the proteases prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) expressed in cancer tissue. The hydrophilic peptide moiety was hypothesized to prevent penetration of the prodrugs into cells and prevent interaction with PKC. Cleavage of the peptide in cancer tumors was envisioned to release lipophilic cytotoxins, which subsequently penetrate into cancer cells. The 4 beta-phorbol esters were prepared from 4 beta-phorbol isolated from Croton tiglium seeds, while the peptides were prepared by solid-phase synthesis. Cellular assays revealed activation of PKC by the prodrugs and efficient killing of both peptidase positive as well as peptidase negative cells. Consequently no selectivity for enzyme expressing cells was found.
Subject: 4 beta-Phorbol ester
protease-assisted targeting
targeted chemotherapy
prodrug
prostate-specific antigen
prostate-specific membrane antigen
PROSTATE-CANCER CELLS
ANTIGEN-ACTIVATED THAPSIGARGIN
DOWN-REGULATION
ANDROGEN RECEPTOR
INDUCED APOPTOSIS
MEMBRANE ANTIGEN
MOLECULAR GRENADES
PKC-EPSILON
DELTA
12-O-TETRADECANOYLPHORBOL-13-ACETATE
317 Pharmacy
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