Thapsigargin, Origin, Chemistry, Structure-Activity Relationships and Prodrug Development

Author(s): Nhu Thi Quynh Doan, Soren Brogger Christensen

Journal Name: Current Pharmaceutical Design

Volume 21 , Issue 38 , 2015

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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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Article Details

Year: 2015
Page: [5501 - 5517]
Pages: 17
DOI: 10.2174/1381612821666151002112824
Price: $65

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