Missing Selectivity of Targeted 4β-Phorbol Prodrugs Expected to be Potential Chemotherapeutics
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Missing Selectivity of Targeted 4β-Phorbol Prodrugs Expected to be Potential Chemotherapeutics. / Tarvainen, Ilari; Zimmermann, Tomas; Heinonen, Pia; Jäntti, Maria Helena ; Yli-Kauhaluoma, Jari; Talman, Virpi; Franzyk, Henrik; Tuominen, Raimo K; Christensen, Søren Brøgger.
In: A C S Medicinal Chemistry Letters, Vol. 11, No. 5, 2020, p. 671-677.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Missing Selectivity of Targeted 4β-Phorbol Prodrugs Expected to be Potential Chemotherapeutics
AU - Tarvainen, Ilari
AU - Zimmermann, Tomas
AU - Heinonen, Pia
AU - Jäntti, Maria Helena
AU - Yli-Kauhaluoma, Jari
AU - Talman, Virpi
AU - Franzyk, Henrik
AU - Tuominen, Raimo K
AU - Christensen, Søren Brøgger
PY - 2020
Y1 - 2020
N2 - Targeting cytotoxic 4β-phorbol esters toward cancer tissue was attempted by conjugating a 4β-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 4β-phorbol esters were prepared from 4β-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.
AB - Targeting cytotoxic 4β-phorbol esters toward cancer tissue was attempted by conjugating a 4β-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 4β-phorbol esters were prepared from 4β-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.
KW - Faculty of Health and Medical Sciences
KW - 4β-Phorbol ester
KW - Protease-assisted targeting
KW - Targeted chemotherapy
KW - Prodrug
KW - Prostate-specific antigen
KW - Prostate-specific membrane antigen
U2 - 10.1021/acsmedchemlett.9b00554
DO - 10.1021/acsmedchemlett.9b00554
M3 - Journal article
C2 - 32435369
VL - 11
SP - 671
EP - 677
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
SN - 1948-5875
IS - 5
ER -
ID: 232592750