Preparation of Enzyme-Activated Thapsigargin Prodrugs by Solid-Phase Synthesis
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Preparation of Enzyme-Activated Thapsigargin Prodrugs by Solid-Phase Synthesis. / Zimmermann, Tomas; Christensen, Søren Brøgger; Franzyk, Henrik.
I: Molecules, Bind 23, Nr. 6, 1463, 15.06.2018.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
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
U2 - 10.3390/molecules23061463
DO - 10.3390/molecules23061463
M3 - Journal article
C2 - 29914143
VL - 23
JO - Molecules
JF - Molecules
SN - 1420-3049
IS - 6
M1 - 1463
ER -
ID: 198571585