Anti-Lymphangiogenic Terpenoids from the Heartwood of Taiwan Juniper, Juniperus chinensis var. tsukusiensis .

To look in-depth into the phytochemical and pharmacological properties of Taiwan juniper, this study investigated the chemical profiles and anti-lymphangiogenic activity of Juniperus chinensis var. tsukusiensis . In this study, four new sesquiterpenes, 12-acetoxywiddrol ( 1 ), cedrol-13-al ( 2 ), α-corocalen-15-oic acid ( 3 ), 1,3,5-bisaoltrien-10-hydroperoxy-11-ol ( 4 ), one new diterpene, 1β,2β-epoxy-9α-hydroxy-8(14),11-totaradiene-3,13-dione ( 5 ), and thirty-three known terpenoids were successfully isolated from the heartwood of J. chinensis var. tsukusiensis . The structures of all isolates were determined through the analysis of physical data (including appearance, UV, IR, and optical rotation) and spectroscopic data (including 1D, 2D NMR, and HRESIMS). Thirty-four compounds were evaluated for their anti-lymphangiogenic effects in human lymphatic endothelial cells (LECs). Among them, totarolone ( 6 ) displayed the most potent anti-lymphangiogenic activity by suppressing cell growth (IC 50 = 6 ± 1 µM) of LECs. Moreover, 3β-hydroxytotarol ( 7 ), 7-oxototarol ( 8 ), and 1-oxo-3β-hydroxytotarol ( 9 ) showed moderate growth-inhibitory effects on LECs with IC 50 values of 29 ± 1, 28 ± 1, and 45 ± 2 µM, respectively. Totarolone ( 6 ) also induced a significant concentration-dependent inhibition of LEC tube formation (IC 50 = 9.3 ± 2.5 µM) without cytotoxicity. The structure-activity relationship discussion of aromatic totarane-type diterpenes against lymphangiogenesis of LECs is also included in this study. Altogether, our findings unveiled the promising potential of J. chinensis var. tsukusiensis in developing therapeutics targeting tumor lymphangiogenesis.