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.
Highlights
Substances able to induce endoplasmic reticulum (ER) stress are suitable tools in cancer research and therapy
Thapsigargin (Tg), which is isolated from Thapsia garganica L. (Apiaceae) [1], induces apoptosis in all types of cancer cell lines [2,3,4] regardless of the phase of the cell cycle [5]
This feature overcomes the drawback of chemotherapeutics such as paclitaxel and docetaxel, currently used in clinics as first- and second-line therapies, which act as mitotic poisons
Summary
Substances able to induce endoplasmic reticulum (ER) stress are suitable tools in cancer research and therapy. (Apiaceae) [1], induces apoptosis in all types of cancer cell lines [2,3,4] regardless of the phase of the cell cycle [5] This feature overcomes the drawback of chemotherapeutics such as paclitaxel and docetaxel, currently used in clinics as first- and second-line therapies, which act as mitotic poisons (reviewed in [6]). In terms of total synthesis, firstly, the number of steps in the published methods for the total synthesis of Tg preclude their use for commercial production, and, secondly, the total yields are rather poor [24,25] Another option is to take advantage of the published procedure for converting nortrilobolide (nTb) into Tg [26,27]. A procedure for the isolation of Tb on the decagram scale is described
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