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Molecules 2018, 23(6), 1463;

Preparation of Enzyme-Activated Thapsigargin Prodrugs by Solid-Phase Synthesis

Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, DK-2100 Copenhagen, Denmark
Present address: Technicka 5, Prague 6, 166 28, UCT Prague, Czech Republic.
Author to whom correspondence should be addressed.
Academic Editor: Viktor Krchnak
Received: 20 May 2018 / Revised: 5 June 2018 / Accepted: 12 June 2018 / Published: 15 June 2018
(This article belongs to the Special Issue Solid Phase Synthesis)
Full-Text   |   PDF [1643 KB, uploaded 15 June 2018]   |  


Since cells in solid tumors divide less rapidly than cells in the bone marrow or cells of the immune system, mitotic inhibitors often cause severe side effects when used for treatment of diseases like prostate cancer and breast cancer. One approach to overcome this problem involves attempts at developing drugs based on general cytotoxins, like calicheamicin and thapsigargin, which kill cells at all phases of the cell cycle. However, such toxins can only be used when efficient targeting to the malignant tissue is possible. In the case of thapsigargin, selectivity for tumor-associated cells is achieved by conjugating the drug to a peptide that is only cleaved in the vicinity of tumors to release the cytotoxic drug or an analog with retained activity. Solid-phase synthesis protocols were developed for preparation of three already validated prodrugs of thapsigargin: one prodrug cleavable by human kallikrein 2, one prodrug cleavable by prostate-specific antigen, and one prodrug cleavable by prostate-specific membrane antigen. View Full-Text
Keywords: prodrug; targeted chemotherapy; thapsigargin; mipsagargin; solid-phase peptide synthesis: cytotoxin-peptide conjugation prodrug; targeted chemotherapy; thapsigargin; mipsagargin; solid-phase peptide synthesis: cytotoxin-peptide conjugation

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Zimmermann, T.; Christensen, S.B.; Franzyk, H. Preparation of Enzyme-Activated Thapsigargin Prodrugs by Solid-Phase Synthesis. Molecules 2018, 23, 1463.

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