Total synthesis of five thapsigargins: guaianolide natural products exhibiting sub-nanomolar SERCA inhibition.
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.
Andrews
Stephen P
SP
University Chemical Laboratory, Lensifield Road, Cambridge, CB2 1EW, UK.
Ball
Matthew
M
Wierschem
Frank
F
Cleator
Ed
E
Oliver
Steven
S
Högenauer
Klemens
K
Simic
Oliver
O
Antonello
Alessandra
A
Hünger
Udo
U
Smith
Martin D
MD
Ley
Steven V
SV
D000475:Alkenes / Q000737:chemistry; D001685:Biological Factors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003500:Cyclization; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D036103:Nanotechnology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D045789:Sesquiterpenes, Guaiane / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D019284:Thapsigargin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology
D000475:Alkenes; D001685:Biological Factors; D004791:Enzyme Inhibitors; D045789:Sesquiterpenes, Guaiane; D019284:Thapsigargin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases