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

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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.
Original languageEnglish
Article number1463
Issue number6
Number of pages13
Publication statusPublished - 15 Jun 2018

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