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 organization: | Division of Pharmacology and Pharmacotherapy Drug Research Program PREP in neurodegenerative disorders Division of Pharmaceutical Chemistry and Technology Pharmaceutical Design and Discovery group Jari Yli-Kauhaluoma / Principal Investigator University Management Regenerative pharmacology group Regenerative cardiac pharmacology |
Date: | 2020-05-14 |
Language: | eng |
Number of pages: | 7 |
Belongs to series: | ACS Medicinal Chemistry Letters |
ISSN: | 1948-5875 |
DOI: | https://doi.org/10.1021/acsmedchemlett.9b00554 |
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 |
Peer reviewed: | Yes |
Usage restriction: | openAccess |
Self-archived version: | acceptedVersion |
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