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.

Department of Drug Design and Pharmacology Faculty of Health and Medical Sciences University of Copenhagen Jagtvej 162 DK 2100 Copenhagen Denmark

Department of Drug Design and Pharmacology Faculty of Health and Medical Sciences University of Copenhagen Jagtvej 162 DK 2100 Copenhagen Denmark Department of Chemistry of Natural Compounds Faculty of Food and Biochemical Technology University of Chemistry and Technology 166 28 Prague Czech Republic

Drug Research Program Division of Pharmaceutical Chemistry and Technology Faculty of Pharmacy University of Helsinki 00100 Helsinki Finland

Drug Research Program Division of Pharmacology and Pharmacotherapy Faculty of Pharmacy University of Helsinki 00100 Helsinki Finland

Drug Research Program Division of Pharmacology and Pharmacotherapy Faculty of Pharmacy University of Helsinki 00100 Helsinki Finland National Heart and Lung Institute Imperial College London London SW7 2AZ United Kingdom

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