ABSTRACT
The difference in reactivity of the hexaoxygenated natural product thapsigargin (1) and the pentaoxygenated nortrilobolide (3) was compared in order to develop a chemo- and regioselective method for the conversion of nortrilobolide (3) into the natural product 2-acetoxytrilobolide (4). For the first time, a stereoselective synthesis of 2-acetoxytrilobolide (4) is described, which involves two key reactions: the first chemical step was a one-pot substitution-oxidation reaction of an allylic ester into its corresponding α,ß-unsaturated ketone. The second process consisted of a stereoselective α'-acyloxylation of the key intermediate α,ß-unsaturated ketone to afford its corresponding acetoxyketone, which was converted into 2-acetoxytrilobolide (4) in a few steps. This innovative approach would allow the synthesis of a broad library of novel and valuable penta- and hexaoxygenated guaianolides as potential anticancer agents.
Subject(s)
Antineoplastic Agents/chemical synthesis , Azulenes/chemistry , Azulenes/chemical synthesis , Sesquiterpenes, Guaiane/chemistry , Sesquiterpenes, Guaiane/chemical synthesis , Thapsia/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Azulenes/pharmacology , Combinatorial Chemistry Techniques , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Sesquiterpenes, Guaiane/pharmacology , Stereoisomerism , Thapsigargin/chemical synthesis , Thapsigargin/chemistry , Thapsigargin/pharmacologyABSTRACT
The skin irritating principle from Thapsia garganica was isolated, named thapsigargin and the structure elucidated. By inhibiting the sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA) thapsigargin provokes apoptosis in almost all cells. By conjugating thapsigargin to peptides, which are only substrates for either prostate specific antigen (PSA) or prostate specific membrane antigen (PSMA) prodrugs were created, which selectively affect prostate cancer cells or neovascular tissue in tumors. One of the prodrug is currently tested in clinical phase II. The prodrug under clinical trial has been named mipsagargin.