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

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

• chemical synthesis
• extraction
• mipsagargin
• trilobolide isolation from fruits
• optimization and scale-up
• <i>Laser trilobum</i> cultivation