Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references
Thapsigargin raises cytosolic (intracellular) calcium concentration by blocking the ability of the cell to pump calcium into the sarcoplasmic and endoplasmic reticula. Store-depletion can secondarily activate plasma membranecalcium channels, allowing an influx of calcium into the cytosol. Depletion of ER calcium stores leads to ER stress and activation of the unfolded protein response.[4] Non-resolved ER stress can cumulatively lead to cell death.[5][6] Prolonged store depletion can protect against ferroptosis via remodeling of ER-synthesized phospholipids.[7]
Thapsigargin treatment and the resulting ER calcium depletion inhibits autophagy independent of the UPR.[8][9]
Thapsigargin is useful in experimentation examining the impacts of increasing cytosolic calcium concentrations and ER calcium depletion.
A study from the University of Nottingham showed promising results for its use against Covid-19 and other coronavirus.
Biosynthesisedit
The complete biosynthesis of thapsigargin has yet to be elucidated. A proposed biosynthesis starts with the farnesyl pyrophosphate. The first step is controlled by the enzyme germacrene B synthase. In the second step, the C(8) position is easily activated for an allylic oxidation due to the position of the double bond. The next step is the addition of the acyloxy moiety by a P450 acetyltransferase; which is a well known reaction for the synthesis of the diterpene, taxol. In the third step, the lactone ring is formed by a cytochrome P450 enzyme using NADP+. With the butyloxy group on the C(8), the formation will only generate the 6,12-lactone ring. The fourth step is an epoxidation that initiates the last step of the base guaianolide formation. In the fifth step, a P450 enzyme closes the 5 + 7 guaianolide structure. The ring closing is important, because it will proceed via 1,10 - epoxidation in order to retain the 4,5 - double bond needed in thapsigargin. It is not known whether the secondary modifications to the guaianolide occur before, or after the formation of thapsigargin, but will need to be considered when elucidating the true biosynthesis. It should also be noted, that several of these enzymes are P450s, therefore oxygen and NADPH are likely crucial to this biosynthesis as well as other cofactors such as Mg2+ and Mn2+ may be needed.[10]
Researchedit
Since inhibition of SERCA is a mechanism of action that has been used to target solid tumors, thapsigargin has attracted research interest. A prodrug of thapsigargin, mipsagargin, is currently undergoing clinical trials for the treatment of glioblastoma.[11][12][13][14]
The biological activity has also attracted research into the laboratory synthesis of thapsigargin. To date, three distinct syntheses have been reported: one by Steven V. Ley,[15] one by Phil Baran.,[16] and one by P. Andrew Evans.[17]
Laboratory studies at the University of Nottingham, using in vitro cell cultures, indicates possible potential as a broad spectrum antiviral, with activity against the COVID-19 virus (SARS-CoV-2), a common cold virus, respiratory syncytial virus (RSV), and the influenza A virus.[20]
^Rogers TB, Inesi G, Wade R, Lederer WJ (1995). "Use of thapsigargin to study Ca2+ homeostasis in cardiac cells". Biosci. Rep. 15 (5): 341–9. doi:10.1007/BF01788366. PMID 8825036. S2CID 29613387.
^Rasmussen U, Brøogger Christensen S, Sandberg F (1978). "Thapsigargine and thapsigargicine, two new histamine liberators from Thapsia garganica L.". Acta Pharm. Suec. 15 (2): 133–140. PMID 79299.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^Hakii H, Fujiki, H., Suganuma, M., Nakayasu, M., Tahira, T., Sugimura, T., Scheuer, P. J., Christensen, S. B. (1986). "Thapsigargin, a histamine secretagogue, is a non-12-O-tetradecanolphorbol-13-acetate (TPA) type tumor promoter in two-stage mouse skin carcinogenesis". Journal of Cancer Research and Clinical Oncology. 111 (3): 177–181. doi:10.1007/BF00389230. PMID 2426275. S2CID 19093742.
^Malhotra JD, Kaufman RJ (December 2007). "The endoplasmic reticulum and the unfolded protein response". Seminars in Cell & Developmental Biology. 18 (6): 716–731. doi:10.1016/j.semcdb.2007.09.003. PMC2706143. PMID 18023214.
^Hetz C, Papa FR (January 2018). "The Unfolded Protein Response and Cell Fate Control". Molecular Cell. 69 (2): 169–181. doi:10.1016/j.molcel.2017.06.017. PMID 29107536.
^Ball M, Andrews SP, Wierschem F, Cleator E, Smith MD, Ley SV (2007). "Total Synthesis of Thapsigargin, a Potent SERCA Pump Inhibitor". Organic Letters. 9 (4): 663–6. doi:10.1021/ol062947x. PMID 17256950.
^Chu H, Smith JM, Felding J, Baran PS (2017). "Scalable Synthesis of (−)-Thapsigargin". ACS Central Science. 3 (1): 47–51. doi:10.1021/acscentsci.6b00313. PMC5269647. PMID 28149952.
^Chen D, Evans PA (2017). "A Concise, Efficient and Scalable Total Synthesis of Thapsigargin and Nortrilobolide from (R)-(-)-Carvone". J. Am. Chem. Soc. 139 (17): 6046–6049. doi:10.1021/jacs.7b01734. PMID 28422492.
^Glushakov AV, Glushakova HY, Skok VI (1999-01-15). "Modulation of nicotinic acetylcholine receptor activity in submucous neurons by intracellular messengers". Journal of the Autonomic Nervous System. 75 (1): 16–22. doi:10.1016/S0165-1838(98)00165-9. ISSN 0165-1838. PMID 9935265 – via https://doi.org/10.1016/S0165-1838(98)00165-9. {{cite journal}}: External link in |via= (help)
^Voitenko SV, Bobryshev AY, Skok VI (2000-01-01). "Intracellular regulation of neuronal nicotinic cholinorceptors". Neuroscience and Behavioral Physiology. 30 (1): 19–25. doi:10.1007/BF02461388. ISSN 0097-0549. PMID 10768368. S2CID 10990124.
^"Powerful Antiviral Treatment for COVID-19 Discovered That Could Change How Epidemics Are Managed". 2 February 2021.
<15.Dey. S.; Bajaj, S. O "Promising anticancer drug thapsigargin: A perspective toward the total synthesis" Synthetic communication 2018, 48(1), 1-13/>