67526-95-8 Usage
Description
Thapsigargin is a naturally occurring sesquiterpene lactone isolated from the umbelliferous plant Thapsia garganica. It is a non-competitive, cell permeable inhibitor of calcium transport by SERCAs (IC50 values are cell type-dependent and range from ~2-80 nM). This tumor promoter releases Ca2+ from intracellular stores by specifically inhibiting the endoplasmic reticulum Ca2+-ATPase; it does not directly affect plasma membrane Ca2+-ATPases, Ins 1,4,5-P3 production or protein kinase C activity. This effect is a result of emptying the intracellular calcium stores, which leads to a chain of events that causes apoptosis.
Chemical Properties
Thapsigargin (TG) is colourless film. It is extracted from the plant Thapsia garganica L. with methanol and purified by HPLC. TG is a tumor promoting plant sesquiterpene lactone extract with a unique biological activity as Ca2+ -ATPase inhibitors in animal cells. It is a skin irritant, a platelet activating, inflammatory and tumor promoting agent. TG is toxic and a possible carcinogen.
Uses
THAPSIGARGIN is a widely used inhibitor of the ubiquitous sarco-endoplasmic reticulum Ca(2+)-ATPases in mammalian cells. It acts as a potent, cell-permeable, IP3-independent intracellular calcium releaser that blocks the transient increase in intracellular Ca2+ induced by angiostatin and endostatin. It induces apoptosis by disrupting intracellular free Ca2+ levels.
Definition
ChEBI: Thapsigargin is an organic heterotricyclic compound that is a hexa-oxygenated 6,7-guaianolide isolated fron the roots of Thapsia garganica L., Apiaceae. A potent skin irritant, it is used in traditional medicine as a counter-irritant. Thapsigargin inhibits Ca(2+)-transporting ATPase mediated uptake of calcium ions into sarcoplasmic reticulum and is used in experimentation examining the impacts of increasing cytosolic calcium concentrations. It has a role as an EC 3.6.3.8 (Ca(2+)-transporting ATPase) inhibitor and a calcium channel blocker. It is a sesquiterpene lactone, an organic heterotricyclic compound and a butyrate ester.
Biochem/physiol Actions
Thapsigargin is an effective inhibitor of calcium ion pumps located on sarcoplasmic reticulum (SR) and endoplasmic reticulum (ER) microsomes of skeletal, cardiac, muscle and brain tissues. The inhibition of calcium ion pumps causes intracellular increase of calcium ion levels. It was found that thapsigargin at 100 nM concentration effectively inhibited the SR Ca2+- adenosine triphosphatase (ATPase) in cardiac and skeletal muscles. Thapsigargin was also reported to be effective in blocking autophagy by interfering with the autophagosome-lysosome fusion.
Mode of action
The actual mechanism of action of thapsigargin is thought actually to block calcium channels in an open conformation that results in excess calcium entry from outside the cell. Excess calcium activates DNAses and precipitates the natural death sequence of the cells.Scientists are now thinking of modifying thapsigargin in such a way thatit will kill prostate cells preferentially and will not penetrate healthy cells elsewhere in the body.At the same time, they are determining whether this drug can also induce cell death in breast cancer cells.
References
1) Treiman et al. (1998), A tool coming of age: thapsigargin as an inhibitor of sarco-endoplasmic reticulum Ca(2+)-ATPases; Trends Pharmacol. Sci., 19 131
2) Zhou et al. (2009), Autophagy-mediated insulin receptor down-regulation contributes to endoplasmic reticulum stress-induced insulin resistance; Mol. Pharmacol., 76 596
Check Digit Verification of cas no
The CAS Registry Mumber 67526-95-8 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 6,7,5,2 and 6 respectively; the second part has 2 digits, 9 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 67526-95:
(7*6)+(6*7)+(5*5)+(4*2)+(3*6)+(2*9)+(1*5)=158
158 % 10 = 8
So 67526-95-8 is a valid CAS Registry Number.
67526-95-8Relevant articles and documents
SYNTHESIS OF THAPSIGARGIN, NORTRILOBOLIDE, AND ANALOGS THEREOF
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, (2018/10/25)
The present invention relates to the preparation of compounds of Formula I, including thapsigargin, nortrilobolide and 8-O-debutanoyl-thapsigargin from commercially available (R)-(-)-carvone via synthetic intermediate compound of formula 12 by pinacol coupling and in situ lactonization.
A Concise, Efficient and Scalable Total Synthesis of Thapsigargin and Nortrilobolide from (R)-(?)-Carvone
Chen, Dezhi,Evans, P. Andrew
, p. 6046 - 6049 (2017/05/09)
A concise, efficient and scalable synthesis of thapsigargin and nortrilobolide from commercially available (R)-(?)-carvone was developed. Our synthetic strategy is inspired by nature’s carbon-carbon bond formation sequence, which facilitates the construction of a highly functionalized sesquiterpene lactone skeleton in five steps via an enantioselective ketone alkylation and a diastereoselective pinacol cyclization. We envision that this strategy will permit the construction of other members of the family, structural analogs and provide a practical synthetic route to these important bioactive agents. In addition, we anticipate that the prodrug Mipsagargin, which is currently in late-stage clinical trials for the treatment of cancer, will also be accessible via this strategy. Hence, the limited availability from natural sources, coupled with an estimated demand of one metric ton per annum for the prodrug, provides a compelling mandate to develop practical total syntheses of these agents.
Total synthesis of thapsigargin, a potent SERCA pump inhibitor
Ball, Matthew,Andrews, Stephen P.,Wierschem, Frank,Cleator, Ed,Smith, Martin D.,Ley, Steven V.
, p. 663 - 666 (2008/02/05)
The enantioselective total synthesis of thapsigargin, a potent, selective inhibitor of the Ca2+ pump SERCA, is described. Starting from ketoalcohol 8, key steps involve regioselective introduction of the internal olefin at C4-C5, judicious protecting group choice to allow chelation-controlled reduction at C3, and chemoselective introduction of the angelate ester function at C3-0. A selective esterification approach completes the total synthesis in a total of 42 steps and 0.61% overall yield (88.6% average yield per step).
