A streamlined strategy was developed to obtain a mixture of thapsigargins from the fruits of Thapsia garganica L. The mixture was resolved by RP-silica gel flash chromatography to provide, after trituration with ether, 0.32% thapsigargin (1a) as a white powder. A novel, complex phenylpropanoid (neohelmanthicin D, 2a) was also obtained, and its structure confirmed by semisynthesis.
For reviews, see: (a) AvatoP. (1997) The genus Thapsia as a source of bioactive compounds, in Virtual Activity, Real Pharmacology (VerottaL. Ed.), Research Signpost, Trivandrum, p. 17–31
2.
(b) BhariLE, MakhloufM. (2001) Thapsia garganica L: A poisonous plant of North Africa. Veterinarian and Human Toxicology, 43, 216–218.
3.
For a review, see: ChristensenSB, AndersenA, SmittUW (1997) Sesquiterpenoids from Thapsia species and medicinal chemistry of the thapsigargins. Progress in the Chemistry of Organic Natural Products, 71, 129–167.
4.
For a recent review, see: ToyoshimaC, InesiG. (2004) Structural basis of ion pumping by Ca2+-ATPase of the sarcoplasmic reticulum. Annual Review Biochemistry, 73, 269–292.
5.
JakobsenCM, DenmeadeSR, IsaacsJT, GadyA, OlsenCE, ChristensenSB. (2001) Design, synthesis, and pharmacological evaluation of thapsigargin analogues for targeting apoptosis to prostatic cancer cells. Journal of Medicinal Chemistry, 44, 4696–4703.
6.
LiuH, JensenKG, TranLM, ChenM, ZhaiL, OlsenCE, SøhoelH, DenmeadeSR, IsaacsJT, ChristensenSB (2006) Cytotoxic phenylpropanoids and an aditional thapsigargin analogue isolated from Thapsia garganica.Phytochemistry, 67, 2651–2658.
7.
BarrettAGM, SmithML, ZecriFJ (1998) Impurity annihilation; a strategy for solution phase combinatorial chemistry with minimal purification. Chemical Communications, 2317–2318.
8.
SmittUW, MoldtP, ChristensenSB (1986) Structure of a pro 1,4-dimethylazulene guaianolide from Thapsia garganica L. Acta Chemica Scandinava, 45, 56–61.
9.
(a) Isolation: SmittUW, ChristensenSB. (1991) Nortrilobolide, a new potent guaianolide segretagogue from Thapsia garganica.Planta Medica, 57, 196–197
10.
(b) Total synthesis: LeySV, AntonelloA, BalkusEP, BoothDT, ChristensenSB, CleatorE, GoldH, HögenauerK, HüngerU, MyersRM, OliverSF, SimicO, SmithMD, SøhoelH, WoolfordAJA. (2004) Synthesis of the thapsigargins. Proceedings of the National Academy of Sciences USA, 101, 12073–12078.
11.
Nortrilobolide shows SERCA-inhibiting properties very similar to those of thapsigargin, and has been successfully employed for the synthesis of second-generation SERCA inhibitors to target prostate cancer cells (SøhoelH, JensenAML, MøllerJV, NissenP, DenmeadeSR, IsaacsJT, OlsenCE, ChristensenSB (2006) Natural products as starting material for development of second-generation SERCA inhibitors targeted towards prostate cancer cells. Bioorganic & Medicinal Chemistry, 14, 2810–2815).
12.
AndersenA, CornettC, LauridsenA, OlsenCE, ChristensenSB. (1994) Selective transformations of the Ca2+ pump inhibitor thapsigargin. Acta Chemica Scandinava, 48, 340–346.
13.
JägerAK, GudiksenL, AdsersenA, SmittUW. (1993) High-performance liquid chromatography of thapsigargins. Journal of Chromatography, 634, 135–137.
14.
ChristensenSB, NorupE, RasmussenU, ÒaardMadsen J. (1984) Structure of histamine releasing guaianolides from Thapsia garganica.Phytochemistry, 23, 1659–1663.
15.
Supplied by Alexis Biochemicals.
16.
Ester acid names: Ang = Angelic acid; But = n-Butanoic acid; Hex = n-Hexanoic acid; Oct = n-Octanoic acid; Dec = n-Decanoic acid; Va l = 3-Methylbutyric (isovalerianic) acid.
