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. 2020 Dec 5;10(12):1640.
doi: 10.3390/biom10121640.

Large Scale Conversion of Trilobolide into the Payload of Mipsagargin: 8- O-(12-Aminododecanoyl)-8- O-Debutanoylthapsigargin

Affiliations

Large Scale Conversion of Trilobolide into the Payload of Mipsagargin: 8- O-(12-Aminododecanoyl)-8- O-Debutanoylthapsigargin

Tomáš Zimmermann et al. Biomolecules. .

Abstract

In spite of the impressing cytotoxicity of thapsigargin (Tg), this compound cannot be used as a chemotherapeutic drug because of general toxicity, causing unacceptable side effects. Instead, a prodrug targeted towards tumors, mipsagargin, was brought into clinical trials. What substantially reduces the clinical potential is the limited access to Tg and its derivatives and cost-inefficient syntheses with unacceptably low yields. Laser trilobum, which contains a structurally related sesquiterpene lactone, trilobolide (Tb), is successfully cultivated. Here, we report scalable isolation of Tb from L. trilobum and a transformation of Tb to 8-O-(12-aminododecanoyl)-8-O-debutanoylthapsigargin in seven steps. The use of cultivated L. trilobum offers an unlimited source of the active principle in mipsagargin.

Keywords: 8-O-(12-aminododecanoyl)-8-O-debutanoylthapsigargin; Laser trilobum cultivation; chemical synthesis; extraction; mipsagargin; optimization and scale-up; sarco/endoplasmic reticulum calcium ATPase (SERCA); sesquiterpene lactones; thapsigargin; trilobolide; trilobolide isolation from fruits.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1
Figure 1
Molecular structures of thapsigargins (Panel A) and structures of researched thapsigargin (Tg) derivatives (Panel B). * 8-O-(12-aminododecanoyl)-8-O-debutanoyl-Tg; ** DEEEE = β-L-Asp-γ-(L-Glu)4-OH.
Figure 2
Figure 2
Optimized route for large scale Tb isolation, i.e., (1) cultivation of L. trilobum and plant harvesting, and (2) drying of fruits and gram-scale isolation of Tb (3).
Scheme 1
Scheme 1
Transformation of Tb to a Tg analog 12ADT (7). Reagents and conditions: (a) CrO3, HF, H2O, MeCN, 95 °C, 2.5 h; (b) octanoic acid, Mn(OAc)3 · 2H2O, 120 °C, 6 h; (c) Zn(BH4)2, Et2O, −20 °C, 3.5 h, followed by H2O; (d) 2,4,6-trichlorobenzoic (Z)-2-methylbut-2-enoic anhydride, NaHCO3, toluene, argon atmosphere, 90 °C, 18 h; (e) TEA, MeOH, 0→20 °C, 21 h, followed by KHSO4; (f) boc-12-aminododecanoic acid, EDC, 4-DMAP, DCM, argon atmosphere, 20 °C, 15 h; (g) TFA, DCM, H2O, 20 °C, 90 min. * Under the arrows, the scale of the starting material is specified in grey.

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