100
S. B. Christensen et al.
These phorbol prodrugs were designed for coadministration with 74–76, since
reports of synergistic enhancement of cell death induced by phorbol and thapsigargin
derivatives have been reported [124–126]. No selectivity for protease-producing and
non-protease producing prostate cancer cells were observed, suggesting that the cell
membrane could not prevent the compounds from interacting with SERCA [218].
13 Perspective
Thapsigargin (1) was isolated in order to explain skin-irritant properties of the ancient
traditional drug Resina Thapsiae, consisting of the resin from the umbelliferous plant
T. garganica. A number of the active principles, all polyoxygenated guaianolides,
were discovered. The major compound obtained was named thapsigargin (1). An
explanation of its skin-irritant properties is that 1 very efficiently releases histamine
from mast cells and mediators from other cells of the immune system. Molecular
pharmacology studies demonstrated that 1 is an extremely potent inhibitor of the
Ca
2+ ATPases situated in the membrane of the endoplasmic or in muscle cells of the
sarcoplasmic reticulum (the SERCA pumps).
Thapsigargin (1) has later become a standard compound for biological assays on
Ca
2+ homeostasis. A search in SciFinder® (Chemical Abstracts Service, Columbus,
Ohio, USA; June 2020) with the keyword thapsigargin gave almost 19,000 hits
and it also gave over 50.000 hits in Google Scholar. This indicates the importance of this plant-derived compound. Complexation of 1 with SERCA also enabled
crystallization of the SERCA pump. This study, when combined with several later
studies, has enabled an understanding of the kinetics and mechanism of action of the
SERCA pump and other P-type ATPases. Studies of thapsigargin-induced apoptosis
have offered biologists new knowledge of the cellular mechanisms behind Ca
2+ -
imbalance- and ER stress-induced cell death. Mipsagargin, a derivative of 1, has
been tested in phase 2 clinical trials as a drug for the treatment of advanced hepatocellular carcinoma. Unfortunately, the targeting of the drug by conjugation with
peptides selectively cleaved by proteases present primarily in cancer tissue did not
sufficiently prevent systemic toxic effects, thus preventing the potential use of the
compound as a drug. However, attempts to conjugate 1 with albumin might resolve
the problem of selectivity [159].
Alternatively, other thapsigargin prodrugs, or other SERCA inhibitors, might be
used. Such inhibitors may be designed by computational chemistry or might be
found in Nature. Other SERCA inhibitors than those related to 1 have been found as
natural products [195, 219]. Unfortunately, neither of these is sufficiently potent for
the prodrug approach.
In addition to the biological studies, intensive studies of 1 have disclosed new
fascinating insight into the guaianolides and their organic chemistry. The targeting
studies of 1 have revealed new and surprising facets of prodrug development, and
the compound has offered invaluable new knowledge on cell function and death.
It has often been mentioned that it is easy to perform important research when one
has been lucky enough to find a unique compound. The answer to this statement is that
S. B. Christensen et al.
These phorbol prodrugs were designed for coadministration with 74–76, since
reports of synergistic enhancement of cell death induced by phorbol and thapsigargin
derivatives have been reported [124–126]. No selectivity for protease-producing and
non-protease producing prostate cancer cells were observed, suggesting that the cell
membrane could not prevent the compounds from interacting with SERCA [218].
13 Perspective
Thapsigargin (1) was isolated in order to explain skin-irritant properties of the ancient
traditional drug Resina Thapsiae, consisting of the resin from the umbelliferous plant
T. garganica. A number of the active principles, all polyoxygenated guaianolides,
were discovered. The major compound obtained was named thapsigargin (1). An
explanation of its skin-irritant properties is that 1 very efficiently releases histamine
from mast cells and mediators from other cells of the immune system. Molecular
pharmacology studies demonstrated that 1 is an extremely potent inhibitor of the
Ca
2+ ATPases situated in the membrane of the endoplasmic or in muscle cells of the
sarcoplasmic reticulum (the SERCA pumps).
Thapsigargin (1) has later become a standard compound for biological assays on
Ca
2+ homeostasis. A search in SciFinder® (Chemical Abstracts Service, Columbus,
Ohio, USA; June 2020) with the keyword thapsigargin gave almost 19,000 hits
and it also gave over 50.000 hits in Google Scholar. This indicates the importance of this plant-derived compound. Complexation of 1 with SERCA also enabled
crystallization of the SERCA pump. This study, when combined with several later
studies, has enabled an understanding of the kinetics and mechanism of action of the
SERCA pump and other P-type ATPases. Studies of thapsigargin-induced apoptosis
have offered biologists new knowledge of the cellular mechanisms behind Ca
2+ -
imbalance- and ER stress-induced cell death. Mipsagargin, a derivative of 1, has
been tested in phase 2 clinical trials as a drug for the treatment of advanced hepatocellular carcinoma. Unfortunately, the targeting of the drug by conjugation with
peptides selectively cleaved by proteases present primarily in cancer tissue did not
sufficiently prevent systemic toxic effects, thus preventing the potential use of the
compound as a drug. However, attempts to conjugate 1 with albumin might resolve
the problem of selectivity [159].
Alternatively, other thapsigargin prodrugs, or other SERCA inhibitors, might be
used. Such inhibitors may be designed by computational chemistry or might be
found in Nature. Other SERCA inhibitors than those related to 1 have been found as
natural products [195, 219]. Unfortunately, neither of these is sufficiently potent for
the prodrug approach.
In addition to the biological studies, intensive studies of 1 have disclosed new
fascinating insight into the guaianolides and their organic chemistry. The targeting
studies of 1 have revealed new and surprising facets of prodrug development, and
the compound has offered invaluable new knowledge on cell function and death.
It has often been mentioned that it is easy to perform important research when one
has been lucky enough to find a unique compound. The answer to this statement is that