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

Tomas Zimmermann; Søren Brøgger Christensen; Henrik Franzyk

doi:10.3390/molecules23061463

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

Tomas Zimmermann, Søren Brøgger Christensen, Henrik Franzyk

5 Citations (Scopus)

43 Downloads (Pure)

Abstract

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 language	English
Article number	1463
Journal	Molecules
Volume	23
Issue number	6
Number of pages	13
ISSN	1420-3049
DOIs	https://doi.org/10.3390/molecules23061463
Publication status	Published - 15 Jun 2018

Keywords

Former Faculty of Pharmaceutical Sciences

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10.3390/molecules23061463

molecules-23-01463Final published version, 1.6 MBLicence: CC BY

Cite this

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title = "Preparation of Enzyme-Activated Thapsigargin Prodrugs by Solid-Phase Synthesis",

abstract = "Since cells in solid tumors divide less rapidly than cells in the bone marrow or cells of theimmune system, mitotic inhibitors often cause severe side effects when used for treatment of diseaseslike prostate cancer and breast cancer. One approach to overcome this problem involves attemptsat developing drugs based on general cytotoxins, like calicheamicin and thapsigargin, which killcells at all phases of the cell cycle. However, such toxins can only be used when efficient targetingto the malignant tissue is possible. In the case of thapsigargin, selectivity for tumor-associated cellsis achieved by conjugating the drug to a peptide that is only cleaved in the vicinity of tumors torelease the cytotoxic drug or an analog with retained activity. Solid-phase synthesis protocols weredeveloped for preparation of three already validated prodrugs of thapsigargin: one prodrug cleavableby human kallikrein 2, one prodrug cleavable by prostate-specific antigen, and one prodrug cleavableby prostate-specific membrane antigen.",

keywords = "Former Faculty of Pharmaceutical Sciences, Prodrugs, targeted chemotherapy, Thapsigargin, Mipsagargin, solid-phase peptide synthesis, Cytotoxin-peptide conjugation",

author = "Tomas Zimmermann and Christensen, {S{\o}ren Br{\o}gger} and Henrik Franzyk",

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T1 - Preparation of Enzyme-Activated Thapsigargin Prodrugs by Solid-Phase Synthesis

AU - Zimmermann, Tomas

AU - Christensen, Søren Brøgger

AU - Franzyk, Henrik

PY - 2018/6/15

Y1 - 2018/6/15

N2 - Since cells in solid tumors divide less rapidly than cells in the bone marrow or cells of theimmune system, mitotic inhibitors often cause severe side effects when used for treatment of diseaseslike prostate cancer and breast cancer. One approach to overcome this problem involves attemptsat developing drugs based on general cytotoxins, like calicheamicin and thapsigargin, which killcells at all phases of the cell cycle. However, such toxins can only be used when efficient targetingto the malignant tissue is possible. In the case of thapsigargin, selectivity for tumor-associated cellsis achieved by conjugating the drug to a peptide that is only cleaved in the vicinity of tumors torelease the cytotoxic drug or an analog with retained activity. Solid-phase synthesis protocols weredeveloped for preparation of three already validated prodrugs of thapsigargin: one prodrug cleavableby human kallikrein 2, one prodrug cleavable by prostate-specific antigen, and one prodrug cleavableby prostate-specific membrane antigen.

AB - Since cells in solid tumors divide less rapidly than cells in the bone marrow or cells of theimmune system, mitotic inhibitors often cause severe side effects when used for treatment of diseaseslike prostate cancer and breast cancer. One approach to overcome this problem involves attemptsat developing drugs based on general cytotoxins, like calicheamicin and thapsigargin, which killcells at all phases of the cell cycle. However, such toxins can only be used when efficient targetingto the malignant tissue is possible. In the case of thapsigargin, selectivity for tumor-associated cellsis achieved by conjugating the drug to a peptide that is only cleaved in the vicinity of tumors torelease the cytotoxic drug or an analog with retained activity. Solid-phase synthesis protocols weredeveloped for preparation of three already validated prodrugs of thapsigargin: one prodrug cleavableby human kallikrein 2, one prodrug cleavable by prostate-specific antigen, and one prodrug cleavableby prostate-specific membrane antigen.

KW - Former Faculty of Pharmaceutical Sciences

KW - Prodrugs

KW - targeted chemotherapy

KW - Thapsigargin

KW - Mipsagargin

KW - solid-phase peptide synthesis

KW - Cytotoxin-peptide conjugation

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