From Plant to Patient: Thapsigargin, a Tool for Understanding …
105
81. Pagani A, Pollastro F, Spera S, Ballero M, Sterner O, Appendino G (2007) An expeditious,
multi-gram isolation protocol for the ultrapotent SERCA inhibitor thapsigargin. Nat Prod
Commun 2:637
82. Ibrahim AMM, Martinez-Swatson KA, Benkaci-Ali F, Cozzi F, Zoulikha F, Simonsen HT
(2018) Effects of γ-irradiation and comparison of different extraction methods on sesquiterpene lactone yields from the medicinal plant Thapsia garganica L. (Apiaceae). J Appl Res
Med Aromat Plants 8:26
83. Lopez CQ, Corral P, Lorrain-Lorrette B, Martinez-Swatson K, Michoux F, Simonsen HT
(2018) Use of a temporary immersion bioreactor system for the sustainable production of
thapsigargin in shoot cultures of Thapsia garganica. Plant Methods 14:79/1
84. Ley SV, Antonello A, Balskus EP, Booth DT, Christensen SB, Cleator E, Gold H, Hoegenauer
K, Huenger U, Myers RM, Oliver SF, Simic O, Smith MD, Sohoel H, Woolford AJA (2004)
Synthesis of the thapsigargins. Proc Natl Acad Sci USA 101:12073
85. Chen D, Evans PA (2017) A concise, efficient and scalable total synthesis of thapsigargin and
nortrilobolide from (R)-(–)-carvone. J Am Chem Soc 139:6046
86. Chu H, Smith JM, Felding J, Baran PS (2017) Scalable synthesis of (−)-thapsigargin. ACS
Cent Sci 347
87. Barton DHR, De Mayo P, Shafiq M (1957) Photochemical transformations. I. Preliminary
investigations. J Chem Soc:929
88. Lauridsen A, Cornett C, Vulpius T, Moldt P, Christensen SB (1996) Syntheses of 11hydroxylated guaianolides. Acta Chem Scand 50:150
89. Manzano FL, Guerra FM, Moreno-Dorado FJ, Jorge ZD, Massanet GM (2006) Toward the
synthesis of thapsigargin: enantioselective synthesis of 7,11-dihydroxyguaianolides. Org Lett
8:2879
90. Lauridsen A, Cornett C, Christensen SB (1991) Exciton coupling in circular dichroic spectroscopy as a tool for establishing the absolute configurtion of α,β-unsaturated esters of allylic
alcohols. Acta Chem Scand 45:56
91. Crestey F, Toma M, Christensen SB (2015) Concise synthesis of thapsigargin from
nortrilobolide. Tetrahedron Lett 56:5896
92. El Bahri L, Makhlouf M (2001) Thapsia garganica L: a poisonous plant of North Africa. Vet
Hum Toxicol 43:216
93. Denmeade SR, Jakobsen CM, Janssen S, Khan SR, Garrett ES, Lilja H, Christensen SB,
Isaacs T (2003) Prostate-specific antigen-activated thapsigargin prodrug as targeted therapy
for prostate cancer. J Natl Cancer Inst 95:990
94. Denmeade SR, Mhaka AM, Rosen DM, Brennen WN, Dalrymple S, Dach I, Olesen C, Gurel
B, DeMarzo AM, Wilding G, Carducci MA Dionne CA, Moeller JV, Nissen P, Christensen
SB, Isaacs JT (2012) Engineering a prostate-specific membrane antigen-activated tumor
endothelial cell prodrug for cancer therapy. Sci Transl Med 4:140ra86
95. Hecker E, Schmidt R (1974) Phorbolesters—the irritants and cocarcinogens of Croton tiglium
L. Fortschr Chem Org Naturst 31:377
96. Fuerstenberger G, Berry DL, Sorg B, Marks F (1981) Skin tumor promotion by phorbol esters
is a two-stage process. Proc Natl Acad Sci USA 78:7722
97. Hakii H, Fujiki H, Suganuma M, Nakayasu M, Tahira T, Sugimura T, Scheuer PJ, Christensen
SB (1986) Thapsigargin, a histamine secretagogue, is a non-12-O- tetradecanoylphorbol-13acetate (TPA) type tumor promoter in two-stage mouse skin carcinogenesis. J Cancer Res
Clin Oncol 111:177
98. Blumberg PM, Jaken S, Konig B, Sharkey NA, Leach KL, Jeng AY, Yeh E (1984) Mechanism
of action of the phorbol ester tumor promoters: specific receptors for lipophilic ligands.
Biochem Pharmacol 33:933
99. Shi Q-W, Su X-H, Kiyota H (2008) Chemical and pharmacological research of the plants in
genus Euphorbia. Chem Rev 108:4295
100. Vasas A, Hohmann J (2014) Euphorbia diterpenes: isolation, structure, biological activity,
and synthesis (2008–2012). Chem Rev 114:8579
105
81. Pagani A, Pollastro F, Spera S, Ballero M, Sterner O, Appendino G (2007) An expeditious,
multi-gram isolation protocol for the ultrapotent SERCA inhibitor thapsigargin. Nat Prod
Commun 2:637
82. Ibrahim AMM, Martinez-Swatson KA, Benkaci-Ali F, Cozzi F, Zoulikha F, Simonsen HT
(2018) Effects of γ-irradiation and comparison of different extraction methods on sesquiterpene lactone yields from the medicinal plant Thapsia garganica L. (Apiaceae). J Appl Res
Med Aromat Plants 8:26
83. Lopez CQ, Corral P, Lorrain-Lorrette B, Martinez-Swatson K, Michoux F, Simonsen HT
(2018) Use of a temporary immersion bioreactor system for the sustainable production of
thapsigargin in shoot cultures of Thapsia garganica. Plant Methods 14:79/1
84. Ley SV, Antonello A, Balskus EP, Booth DT, Christensen SB, Cleator E, Gold H, Hoegenauer
K, Huenger U, Myers RM, Oliver SF, Simic O, Smith MD, Sohoel H, Woolford AJA (2004)
Synthesis of the thapsigargins. Proc Natl Acad Sci USA 101:12073
85. Chen D, Evans PA (2017) A concise, efficient and scalable total synthesis of thapsigargin and
nortrilobolide from (R)-(–)-carvone. J Am Chem Soc 139:6046
86. Chu H, Smith JM, Felding J, Baran PS (2017) Scalable synthesis of (−)-thapsigargin. ACS
Cent Sci 347
87. Barton DHR, De Mayo P, Shafiq M (1957) Photochemical transformations. I. Preliminary
investigations. J Chem Soc:929
88. Lauridsen A, Cornett C, Vulpius T, Moldt P, Christensen SB (1996) Syntheses of 11hydroxylated guaianolides. Acta Chem Scand 50:150
89. Manzano FL, Guerra FM, Moreno-Dorado FJ, Jorge ZD, Massanet GM (2006) Toward the
synthesis of thapsigargin: enantioselective synthesis of 7,11-dihydroxyguaianolides. Org Lett
8:2879
90. Lauridsen A, Cornett C, Christensen SB (1991) Exciton coupling in circular dichroic spectroscopy as a tool for establishing the absolute configurtion of α,β-unsaturated esters of allylic
alcohols. Acta Chem Scand 45:56
91. Crestey F, Toma M, Christensen SB (2015) Concise synthesis of thapsigargin from
nortrilobolide. Tetrahedron Lett 56:5896
92. El Bahri L, Makhlouf M (2001) Thapsia garganica L: a poisonous plant of North Africa. Vet
Hum Toxicol 43:216
93. Denmeade SR, Jakobsen CM, Janssen S, Khan SR, Garrett ES, Lilja H, Christensen SB,
Isaacs T (2003) Prostate-specific antigen-activated thapsigargin prodrug as targeted therapy
for prostate cancer. J Natl Cancer Inst 95:990
94. Denmeade SR, Mhaka AM, Rosen DM, Brennen WN, Dalrymple S, Dach I, Olesen C, Gurel
B, DeMarzo AM, Wilding G, Carducci MA Dionne CA, Moeller JV, Nissen P, Christensen
SB, Isaacs JT (2012) Engineering a prostate-specific membrane antigen-activated tumor
endothelial cell prodrug for cancer therapy. Sci Transl Med 4:140ra86
95. Hecker E, Schmidt R (1974) Phorbolesters—the irritants and cocarcinogens of Croton tiglium
L. Fortschr Chem Org Naturst 31:377
96. Fuerstenberger G, Berry DL, Sorg B, Marks F (1981) Skin tumor promotion by phorbol esters
is a two-stage process. Proc Natl Acad Sci USA 78:7722
97. Hakii H, Fujiki H, Suganuma M, Nakayasu M, Tahira T, Sugimura T, Scheuer PJ, Christensen
SB (1986) Thapsigargin, a histamine secretagogue, is a non-12-O- tetradecanoylphorbol-13acetate (TPA) type tumor promoter in two-stage mouse skin carcinogenesis. J Cancer Res
Clin Oncol 111:177
98. Blumberg PM, Jaken S, Konig B, Sharkey NA, Leach KL, Jeng AY, Yeh E (1984) Mechanism
of action of the phorbol ester tumor promoters: specific receptors for lipophilic ligands.
Biochem Pharmacol 33:933
99. Shi Q-W, Su X-H, Kiyota H (2008) Chemical and pharmacological research of the plants in
genus Euphorbia. Chem Rev 108:4295
100. Vasas A, Hohmann J (2014) Euphorbia diterpenes: isolation, structure, biological activity,
and synthesis (2008–2012). Chem Rev 114:8579