ABSTRACT
Herein we describe the total synthesis of five guaianolide natural products: thapsigargin, thapsivillosin C, thapsivillosin F, trilobolide and nortrilobolide. Prodrug derivatives of thapsigargin have shown selective in vivo cytotoxicity against prostate tumours and the need for further investigation of this phenomenon highlights the importance of these total syntheses. The first absolute stereochemical assignment of thapsivillosin C is also delineated.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Sarcoplasmic Reticulum Calcium-Transporting ATPases/antagonists & inhibitors , Sesquiterpenes, Guaiane/chemical synthesis , Thapsigargin/chemical synthesis , Alkenes/chemistry , Biological Factors/chemical synthesis , Biological Factors/chemistry , Biological Factors/pharmacology , Cyclization , Dose-Response Relationship, Drug , Endoplasmic Reticulum/enzymology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Molecular Structure , Nanotechnology , Sarcoplasmic Reticulum Calcium-Transporting ATPases/chemistry , Sesquiterpenes, Guaiane/chemistry , Sesquiterpenes, Guaiane/pharmacology , Stereoisomerism , Thapsigargin/analogs & derivatives , Thapsigargin/pharmacologyABSTRACT
The thapsigargins are a family of complex guaianolides with potent and selective Ca(2+)-modulating properties. This article documents the evolution of a synthetic route through several iterations to a final practical and scaleable synthetic route capable of generating both unnatural and natural products based around the guaianolide skeleton.
