Thapsigargin was originally isolated from the roots of the Mediterranean umbelliferous plant Thapsia
garganica in order to characterize the skin irritant principle. Characteristic chemical properties and semi-syntheses
are reviewed. The biological activity was related to the subnanomolar affinity for the sarco/endoplasmic reticulum
calcium ATPase. Prolonged inhibition of the pump afforded collapse of the calcium homeostasis and eventually
apoptosis. Structure-activity relationships enabled design of an equipotent analogue containing a linker. Conjugation
of the analogue containing the linker with peptides, which only are substrates for either prostate specific antigen
(PSA) or prostate specific membrane antigen (PSMA) enabled design of prodrugs targeting a number of cancer
diseases including prostate cancer (G115) and hepatocellular carcinoma (G202). Prodrug G202 has under the name
of mipsagargin in phase II clinical trials shown promising properties against hepatocellular carcinoma.
Keywords: Thapsigargin, mipsagargin, drug development, clinical trials, structure activity relationships, prostate specific antigen, prostate
specific membrane antigen, prodrug, anti-angiogenesis.
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