Details
| Stereochemistry | ABSOLUTE |
| Molecular Formula | C34H50O12 |
| Molecular Weight | 650.7536 |
| Optical Activity | UNSPECIFIED |
| Defined Stereocenters | 8 / 8 |
| E/Z Centers | 1 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
CCCCCCCC(=O)O[C@@H]1[C@@H](OC(=O)C(\C)=C/C)C(C)=C2[C@@H]3OC(=O)[C@@](C)(O)[C@@]3(O)[C@H](C[C@](C)(OC(C)=O)[C@@H]12)OC(=O)CCC
InChI
InChIKey=IXFPJGBNCFXKPI-FSIHEZPISA-N
InChI=1S/C34H50O12/c1-9-12-13-14-15-17-24(37)43-28-26-25(20(5)27(28)44-30(38)19(4)11-3)29-34(41,33(8,40)31(39)45-29)22(42-23(36)16-10-2)18-32(26,7)46-21(6)35/h11,22,26-29,40-41H,9-10,12-18H2,1-8H3/b19-11-/t22-,26+,27-,28-,29-,32-,33+,34+/m0/s1
| Molecular Formula | C34H50O12 |
| Molecular Weight | 650.7536 |
| Charge | 0 |
| Count |
|
| Stereochemistry | ABSOLUTE |
| Additional Stereochemistry | No |
| Defined Stereocenters | 8 / 8 |
| E/Z Centers | 1 |
| Optical Activity | UNSPECIFIED |
DescriptionCurator's Comment: description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/27115568
Curator's Comment: description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/27115568
The sesquiterpene lactone thapsigargin is found in the plant Thapsia garganica L., and is one of the major constituents of the roots and fruits of this Mediterranean species. In 1978, the first pharmacological effects of thapsigargin were established and the full structure was elucidated in 1985. Thapsigargin is a potent inhibitor of Sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) and is widely used to study Ca2+-signaling. Thapsigargin is a non-cell-type specific toxin with documented ability to kill a broad spectrum of cancer cell lines as well as normal endothelial cells, fibroblasts and osteoblasts. It induces a rapid and pronounced increase in the concentration of cytosolic calcium, due to blockade of the Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase (SERCA) pump to which it binds with high affinity. The increase in cytosolic calcium leads to induction of apoptosis and ensuing cell death. A prodrug, G-202 (mipsagargin) has been designed to target the blood vessels of cancer cells; the death of these blood vessels then leads to tumor necrosis. G-202 consists of a cytotoxic analog of thapsigargin coupled to a masking peptide which inhibits its biologic activity until proteolytic cleavage at the tumor site. The first clinical trials of this drug were initiated in 2008 for the treatment Advanced Solid Tumors.
Approval Year
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
Target ID: Q64578 Gene ID: 116601.0 Gene Symbol: Atp2a1 Target Organism: Rattus norvegicus (Rat) |
|||
Target ID: P11507 Gene ID: 29693.0 Gene Symbol: Atp2a2 Target Organism: Rattus norvegicus (Rat) |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Primary | Unknown Approved UseUnknown |
PubMed
| Title | Date | PubMed |
|---|---|---|
| Role of calcium in lipopolysaccharide-induced calcitonin gene expression in human adipocytes. | 2011-08 |
|
| Gadolinium-induced oxidative stress triggers endoplasmic reticulum stress in rat cortical neurons. | 2011-04 |
|
| Induction of ER stress protects gastric cancer cells against apoptosis induced by cisplatin and doxorubicin through activation of p38 MAPK. | 2011-03-11 |
|
| Subtilase cytotoxin activates MAP kinases through PERK and IRE1 branches of the unfolded protein response. | 2011-03 |
|
| Involvement of the epidermal growth factor receptor in Pb²+-induced activation of cPLA₂/COX-2 genes and PGE₂ production in vascular smooth muscle cells. | 2011-01-11 |
|
| Long isoforms of NRF1 contribute to arsenic-induced antioxidant response in human keratinocytes. | 2011-01 |
|
| Pathological adaptive responses of Schwann cells to endoplasmic reticulum stress in bortezomib-induced peripheral neuropathy. | 2010-12 |
|
| Rosiglitazone induces the unfolded protein response, but has no significant effect on cell viability, in monocytic and vascular smooth muscle cells. | 2010-10-01 |
|
| Protective effect of melatonin on oxaliplatin-induced apoptosis through sustained Mcl-1 expression and anti-oxidant action in renal carcinoma Caki cells. | 2010-10 |
|
| Hairless expression attenuates apoptosis in a mouse model and the COS cell line; involvement of p53. | 2010-09-23 |
|
| Apigenin protects HT22 murine hippocampal neuronal cells against endoplasmic reticulum stress-induced apoptosis. | 2010-09 |
|
| Implication of TAp73 in the p53-independent pathway of Puma induction and Puma-dependent apoptosis in primary cortical neurons. | 2010-08 |
|
| The JNK pathway modulates expression and phosphorylation of 4E-BP1 in MIN6 pancreatic beta-cells under oxidative stress conditions. | 2010-07 |
|
| eIF5A promotes translation elongation, polysome disassembly and stress granule assembly. | 2010-04-01 |
|
| Lead induces the expression of endoplasmic reticulum chaperones GRP78 and GRP94 in vascular endothelial cells via the JNK-AP-1 pathway. | 2010-04 |
|
| Regulation of endoplasmic reticulum stress-induced cell death by ATF4 in neuroectodermal tumor cells. | 2010-02-26 |
|
| Melatonin reduces apoptosis induced by calcium signaling in human leukocytes: Evidence for the involvement of mitochondria and Bax activation. | 2010-02 |
|
| Multidrug resistance protein transporter and Ins(1,4,5)P₃-sensitive Ca²+-signaling involved in adenosine triphosphate export via Gq protein-coupled NK₂-receptor stimulation with neurokinin A. | 2010 |
|
| Capsaicin inhibits the IL-6/STAT3 pathway by depleting intracellular gp130 pools through endoplasmic reticulum stress. | 2009-05-01 |
|
| The genome-wide expression profile of Scrophularia ningpoensis-treated thapsigargin-stimulated U-87MG cells. | 2009-05 |
|
| Effects of thapsigargin and phenylephrine on calcineurin and protein kinase C signaling functions in cardiac myocytes. | 2009-05 |
|
| Inhibition of mitochondrial function induces an integrated stress response in oligodendroglia. | 2009-05 |
|
| Protective effect of quercetin on ER stress caused by calcium dynamics dysregulation in intestinal epithelial cells. | 2009-04-28 |
|
| Human hnRNP Q re-localizes to cytoplasmic granules upon PMA, thapsigargin, arsenite and heat-shock treatments. | 2009-04-01 |
|
| Endoplasmic reticulum stress-mediated autophagy/apoptosis induced by capsaicin (8-methyl-N-vanillyl-6-nonenamide) and dihydrocapsaicin is regulated by the extent of c-Jun NH2-terminal kinase/extracellular signal-regulated kinase activation in WI38 lung epithelial fibroblast cells. | 2009-04 |
|
| Protective effect against Parkinson's disease-related insults through the activation of XBP1. | 2009-02-27 |
|
| PKD1 haploinsufficiency is associated with altered vascular reactivity and abnormal calcium signaling in the mouse aorta. | 2009-02 |
|
| Role of endoplasmic reticulum stress in acrolein-induced endothelial activation. | 2009-01-01 |
|
| Inhibition of alpha-mannosidase attenuates endoplasmic reticulum stress-induced neuronal cell death. | 2009-01 |
|
| La3+ binds to BiP/GRP78 and induces unfolded protein response in HepG2 cells. | 2008-11-25 |
|
| Suppression of cytokine responses by indomethacin in podocytes: a mechanism through induction of unfolded protein response. | 2008-11 |
|
| Direct activation of transient receptor potential vanilloid 1(TRPV1) by diacylglycerol (DAG). | 2008-10-01 |
|
| Nicotine suppresses tunicamycin-induced, but not thapsigargin-induced, expression of GRP78 during ER stress-mediated apoptosis in PC12 cells. | 2008-08 |
|
| Metabotropic receptor-activated calcium increases and store-operated calcium influx in mouse Müller cells. | 2008-07 |
|
| STIM1 regulates acidic Ca2+ store refilling by interaction with SERCA3 in human platelets. | 2008-06-01 |
|
| Selenoprotein T is a PACAP-regulated gene involved in intracellular Ca2+ mobilization and neuroendocrine secretion. | 2008-06 |
|
| Store-operated Ca(2+) channels and Stromal Interaction Molecule 1 (STIM1) are targets for the actions of bile acids on liver cells. | 2008-05 |
|
| Degradation of caspase-activated DNase by the ubiquitin-proteasome system. | 2008-05 |
|
| Proteasome-dependent pharmacological rescue of cystic fibrosis transmembrane conductance regulator revealed by mutation of glycine 622. | 2008-04 |
|
| The role of diacylglyceride generation by phospholipase D and phosphatidic acid phosphatase in the activation of 5-lipoxygenase in polymorphonuclear leukocytes. | 2008-04 |
|
| Role of phospholipase Cgamma-induced activation of protein kinase Cepsilon (PKCepsilon) and PKCbetaI in epidermal growth factor-mediated protection of tight junctions from acetaldehyde in Caco-2 cell monolayers. | 2008-02-08 |
|
| Altered threshold of the mitochondrial permeability transition pore in Ullrich congenital muscular dystrophy. | 2008-01-30 |
|
| Destabilization of parathyroid hormone mRNA by extracellular Ca2+ and the calcimimetic R-568 in parathyroid cells: role of cytosolic Ca and requirement for gene transcription. | 2008-01 |
|
| Arsenic trioxide initiates ER stress responses, perturbs calcium signalling and promotes apoptosis in human lens epithelial cells. | 2007-12 |
|
| Role of Ca2+-independent phospholipase A2 and store-operated pathway in urocortin-induced vasodilatation of rat coronary artery. | 2007-11-26 |
|
| Translational repression of MCL-1 couples stress-induced eIF2 alpha phosphorylation to mitochondrial apoptosis initiation. | 2007-08-03 |
|
| Mechanisms of resistance and adaptation to thapsigargin in androgen-independent prostate cancer PC3 and DU145 cells. | 2007-08-01 |
|
| Tauroursodeoxycholic acid inhibits apoptosis induced by Z alpha-1 antitrypsin via inhibition of Bad. | 2007-08 |
|
| Vaticanol B, a resveratrol tetramer, regulates endoplasmic reticulum stress and inflammation. | 2007-07 |
|
| Activation profiles of HSPA5 during the glomerular mesangial cell stress response to chemical injury. | 2007 |
Sample Use Guides
Patients with advanced solid tumours received mipsagargin (prodrug of thapsigargin) by intravenous infusion on days 1, 2 and 3 of 28-day cycles and were allowed to continue participation in the absence of disease progression or unacceptable toxicity. The dosing began at 1.2 mg m(-2) and was escalated using a modified Fibonacci schema to determine maximally tolerated dose (MTD) with an expansion cohort at the RP2D.
Route of Administration:
Intravenous
It was investigated cytotoxicity, oxidative stress and inflammatory responses in ZnO nanoparticles (NP) exposed human umbilical vein endothelial cells (HUVECs) with or without the presence of thapsigargin (TG). The presence of 250 nM TG significantly induced cytotoxicity, release of IL-6 and THP-1 monocyte adhesion (p < 0.01), but did not significantly affect intracellular ROS or release of TNFα (p > 0.05). ANOVA analysis indicated no interaction between exposure to ZnO NPs and the presence of TG on almost all the endpoints (p > 0.05) except neutral red uptake assay (p < 0.01)
| Substance Class |
Chemical
Created
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Edited
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| Record UNII |
Z96BQ26RZD
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| Record Status |
Validated (UNII)
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| Record Version |
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DTXSID5040621
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C128634
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ACTIVE MOIETY |
