From Plant to Patient: Thapsigargin, a Tool for Understanding Natural Product Chemistry, Total Syntheses, Biosynthesis, Taxonomy, ATPases, Cell Death, and Drug Development
Publikation: Bidrag til tidsskrift › Review › Forskning › fagfællebedømt
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From Plant to Patient: Thapsigargin, a Tool for Understanding Natural Product Chemistry, Total Syntheses, Biosynthesis, Taxonomy, ATPases, Cell Death, and Drug Development. / Christensen, Søren Brøgger; Simonsen, Henrik Toft; Engedal, Nikolaj; Nissen, Poul; Møller, Jesper Vuust; Denmeade, Samuel R.; Isaacs, John T.
I: Progress in the chemistry of organic natural products, Bind 115, 2021, s. 59-114.Publikation: Bidrag til tidsskrift › Review › Forskning › fagfællebedømt
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T1 - From Plant to Patient: Thapsigargin, a Tool for Understanding Natural Product Chemistry, Total Syntheses, Biosynthesis, Taxonomy, ATPases, Cell Death, and Drug Development
AU - Christensen, Søren Brøgger
AU - Simonsen, Henrik Toft
AU - Engedal, Nikolaj
AU - Nissen, Poul
AU - Møller, Jesper Vuust
AU - Denmeade, Samuel R.
AU - Isaacs, John T.
PY - 2021
Y1 - 2021
N2 - Thapsigargin, the first representative of the hexaoxygenated guaianolides, was isolated 40 years ago in order to understand the skin-irritant principles of the resin of the umbelliferous plant Thapsia garganica. The pronounced cytotoxicity of thapsigargin is caused by highly selective inhibition of the intracellular sarco-endoplasmic Ca2+-ATPase (SERCA) situated on the membrane of the endo- or sarcoplasmic reticulum. Thapsigargin is selective to the SERCA pump and to a minor extent the secretory pathway Ca2+/Mn2+ ATPase (SPCA) pump. Thapsigargin has become a tool for investigation of the importance of SERCA in intracellular calcium homeostasis. In addition, complex formation of thapsigargin with SERCA has enabled crystallization and structure determination of calcium-free states by X-ray crystallography. These results led to descriptions of the mechanism of action and kinetic properties of SERCA and other ATPases. Inhibition of SERCA depletes Ca2+ from the sarco- and endoplasmic reticulum provoking the unfolded protein response, and thereby has enabled new studies on the mechanism of cell death. Development of protocols for selective transformation of thapsigargin disclosed the chemistry and facilitated total synthesis of the molecule. Conversion of trilobolide into thapsigargin offered an economically feasible sustainable source of thapsigargin, which enables a future drug production. Principles for prodrug development were used by conjugating a payload derived from thapsigargin with a hydrophilic peptide selectively cleaved by proteases in the tumor. Mipsagargin was developed in order to obtain a drug for treatment of cancer diseases characterized by the presence of prostate specific membrane antigen (PSMA) in the neovascular tissue of the tumors. Even though mipsagargin showed interesting clinical effects the results did not encourage funding and consequently the attempt to register the drug has been abandoned. In spite of this disappointing fact, the research performed to develop the drug has resulted in important scientific discoveries concerning the chemistry, biosynthesis and biochemistry of sesquiterpene lactones, the mechanism of action of ATPases including SERCA, mechanisms for cell death caused by the unfolded protein response, and the use of prodrugs for cancer-targeting cytotoxins. The presence of toxins in only some species belonging to Thapsia also led to a major revision of the taxonomy of the genus.
AB - Thapsigargin, the first representative of the hexaoxygenated guaianolides, was isolated 40 years ago in order to understand the skin-irritant principles of the resin of the umbelliferous plant Thapsia garganica. The pronounced cytotoxicity of thapsigargin is caused by highly selective inhibition of the intracellular sarco-endoplasmic Ca2+-ATPase (SERCA) situated on the membrane of the endo- or sarcoplasmic reticulum. Thapsigargin is selective to the SERCA pump and to a minor extent the secretory pathway Ca2+/Mn2+ ATPase (SPCA) pump. Thapsigargin has become a tool for investigation of the importance of SERCA in intracellular calcium homeostasis. In addition, complex formation of thapsigargin with SERCA has enabled crystallization and structure determination of calcium-free states by X-ray crystallography. These results led to descriptions of the mechanism of action and kinetic properties of SERCA and other ATPases. Inhibition of SERCA depletes Ca2+ from the sarco- and endoplasmic reticulum provoking the unfolded protein response, and thereby has enabled new studies on the mechanism of cell death. Development of protocols for selective transformation of thapsigargin disclosed the chemistry and facilitated total synthesis of the molecule. Conversion of trilobolide into thapsigargin offered an economically feasible sustainable source of thapsigargin, which enables a future drug production. Principles for prodrug development were used by conjugating a payload derived from thapsigargin with a hydrophilic peptide selectively cleaved by proteases in the tumor. Mipsagargin was developed in order to obtain a drug for treatment of cancer diseases characterized by the presence of prostate specific membrane antigen (PSMA) in the neovascular tissue of the tumors. Even though mipsagargin showed interesting clinical effects the results did not encourage funding and consequently the attempt to register the drug has been abandoned. In spite of this disappointing fact, the research performed to develop the drug has resulted in important scientific discoveries concerning the chemistry, biosynthesis and biochemistry of sesquiterpene lactones, the mechanism of action of ATPases including SERCA, mechanisms for cell death caused by the unfolded protein response, and the use of prodrugs for cancer-targeting cytotoxins. The presence of toxins in only some species belonging to Thapsia also led to a major revision of the taxonomy of the genus.
KW - Faculty of Health and Medical Sciences
KW - Thapsigargin
KW - Mipsagargin
KW - Drug development
KW - SERCA
KW - Taxonomy
KW - APOPTOSIS
KW - drug development
KW - Mipsagargin
KW - SERCA
KW - Prodrugs
KW - Targeted chemotherapy
U2 - 10.1007/978-3-030-64853-4_2
DO - 10.1007/978-3-030-64853-4_2
M3 - Review
C2 - 33797641
VL - 115
SP - 59
EP - 114
JO - Fortschritte der Chemie Organischer Naturstoffe
JF - Fortschritte der Chemie Organischer Naturstoffe
SN - 0071-7886
ER -
ID: 259514368