Phosphaisocoumarins as a new class of potent inhibitors for pancreatic cholesterol esterase.
Due to the importance of pancreatic cholesterol esterase (CEase) as a potential target in atherosclerosis and for the development of hypocholesterolemic agents, there are increasing interests in designing and synthesizing CEase inhibitors. In the present study, we prepared forty-five isocoumarin phosphorus analogues (i.e., phosphaisocoumarins) and investigated the inhibition of these compounds on the CEase. The results showed that some phosphaisocoumarins could act as potent inhibitors of CEase. The most potent inhibitors, compounds 9d, 10a and 12e give IC50 values of 4.8 microM, 2.3 microM and 1.9 microM, respectively. The inhibition mechanism and kinetic characterization studies indicate that they are reversible competitive inhibitors.
School of Chemistry & Chemical Engineering, Sun Yat-sen University, 135 Xingangxi Lu, Guangzhou 510275, China.
Baojian
B
Li
Binhua
B
Zhou
Hailiang
H
Lu
Lin
L
Ma
Ai-Yun
AY
Peng
D000818:Animals; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049934:Isocoumarins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D015394:Molecular Structure; D010179:Pancreas / Q000201:enzymology*; D013237:Stereoisomerism; D002787:Sterol Esterase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013552:Swine
D004791:Enzyme Inhibitors; D049934:Isocoumarins; D002787:Sterol Esterase