Human ACAT inhibitory effects of shikonin derivatives from Lithospermum erythrorhizon

Three naphthoquinones were isolated by bioassay-guided fractionation from the CHCl3 extracts of roots of Lithospermum erythrorhizon. They were identified as acetylshikonin (1), isobutyrylshikonin (2), and β-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 (IC50 = 57.5 μM) than hACAT-1 (32% at 120 μM), 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.

Among the tested shikonin derivatives (1–11), isobutanoyl-substituted analogue 2 preferentially inhibited hACAT-2 with an IC50 value of 57.5 μM, and n-propanoyl- and 3-methylbutanoyl-substituted compounds 5 and 7 showed strong inhibitory activities in both 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.Figure optionsDownload as PowerPoint slide