title: Thapsigargin, Origin, Chemistry, Structure-Activity Relationships and Prodrug Development.
abstract: 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.
authors.forename: Nhu Thi
authors.initials: NT
authors.lastname: Quynh Doan
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences University of Copenhagen, Universitetsparken 2, DK-2100 Copehagen O, Denmark. soren.christensen@sund.ku.dk.
authors.forename: Soren Brogger
authors.initials: SB
authors.lastname: Christensen
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic / Q000379:methods; D055808:Drug Discovery / Q000379:methods*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D019284:Thapsigargin / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D011355:Prodrugs; D019284:Thapsigargin