Structure-activity relationships of analogues of thapsigargin modified at O-11 and O-12.
A number of analogues of thapsigargin have been synthesized by alkylating or acylating O-11 and O-12 in the lactol obtained by reducing thapsigargicin. Introduction of alpha-disposed substituents decreased the Ca(2+)-ATPase inhibitory potency of the analogue, whereas the enzyme was more tolerant toward beta-disposed substituents, indicating that the alpha-face of the lactone ring is in close contact with the binding site when the inhibitor is bound to the enzyme.
Nielsen
S F
SF
Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Copenhagen.
Thastrup
O
O
Pedersen
R
R
Olsen
C E
CE
Christensen
S B
SB
D000818:Animals; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D009132:Muscles / Q000201:enzymology; D011817:Rabbits; D013329:Structure-Activity Relationship; D013729:Terpenes / Q000737:chemistry; D019284:Thapsigargin
D013729:Terpenes; D019284:Thapsigargin; D000252:Calcium-Transporting ATPases