Asymmetric synthesis of pochonin E and F, revision of their proposed structure, and their conversion to potent Hsp90 inhibitors.
A concise and modular synthesis of pochonin E and F, and their epimers at C-6 established the correct stereochemistry of these two natural products. Several members of the pochonin family have been shown to bind the heat shock protein 90 (Hsp90), which has been the focus of intense drug discovery efforts. Pochonin E and F as well as their epimers were derivatized into the corresponding pochoximes and further modified at the C-6 position. Molecular dynamics simulations, docking studies, and Hsp90 affinity measurements were performed to evaluate the impact of these modifications.
Institut de Science et Ingénierie Supramoléculaires (ISIS-UMR 7006), Université de Strasbourg CNRS, 8 Allée Gaspard Monge, 67000 Strasbourg, France.
Ganesan
G
Karthikeyan
Claudio
C
Zambaldo
Sofia
S
Barluenga
Vincent
V
Zoete
Martin
M
Karplus
Nicolas
N
Winssinger
D018360:Crystallography, X-Ray; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry*; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D018841:HSP90 Heat-Shock Proteins; D018942:Macrolides