Human ACAT inhibitory effects of shikonin derivatives from Lithospermum erythrorhizon.
Three naphthoquinones were isolated by bioassay-guided fractionation from the CHCl(3) extracts of roots of Lithospermum erythrorhizon. They were identified as acetylshikonin (1), isobutyrylshikonin (2), and beta-hydroxyisovalerylshikonin (3) on the basis of their spectroscopic analyses. The compounds 1-3 were tested for their inhibitory activities against human ACAT-1 (hACAT-1) or human ACAT-2 (hACAT-2). Compound 2 preferentially inhibited hACAT-2 (IC(50)=57.5microM) than hACAT-1 (32% at 120microM), whereas compounds 1 and 3 showed weak inhibitory activities in both hACAT-1 and -2. To develop more potent hACAT inhibitor, shikonin derivatives (5-11) were synthesized by semi-synthesis of shikonin (4), which was prepared by hydrolysis of 1-3. Among them, compounds 5 and 7 exhibited the strong inhibitory activities against hACAT-1 and -2. Furthermore, we demonstrated that compound 7 behaved as a potent ACAT inhibitor in not only in vitro assay system but also cell-based assay system.
An
Sojin
S
National Research Laboratory of Lipid Metabolism and Atherosclerosis, KRIBB, Daejeon 305-806, Republic of Korea.
Park
Yong-Dae
YD
Paik
Young-Ki
YK
Jeong
Tae-Sook
TS
Lee
Woo Song
WS
D002725:Chloroform; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D029684:Lithospermum / Q000737:chemistry*; D008856:Microscopy, Fluorescence; D009285:Naphthoquinones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D018517:Plant Roots / Q000737:chemistry; D012997:Solvents; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009285:Naphthoquinones; D012997:Solvents; C016101:shikonin; D002725:Chloroform; D002785:Sterol O-Acyltransferase