Terpenoids with vasorelaxant effects from the Chinese liverwort Scapania carinthiaca

Four new diterpenoids scapanacins A-D (1-4) including one kaurane and three clerodane derivatives, along with eleven known compounds (9-15), were isolated from the Chinese liverwort Scapania carinthiaca J.B. Jack ex Lindb. Their structures were determined based on extensive spectroscopic analyses, and electronic circular dichroism (ECD) calculations. Vasorelaxant activity assays of the clerodane-type diterpenoids 2, and 4-8 revealed that they relaxed 3^rd-order rat mesenteric arterioles pre-contracted with norepinephrine (NE). Further assays with scapanacin D (4) confirmed that the vasodilatation was mediated through inhibition of Ca²⁺ influx via voltage-dependent Ca²⁺ channels (VDCs), and this Ca²⁺ channel blocking effect was also confirmed by inhibiting the extracellular Ca²⁺ influx in MOVAS cells. Besides, very little decrease of the relaxant activity caused by 4 on endothelium-denuded mesenteric arterioles with NE also suggested the vasodilatation was mainly produced by inhibiting Ca²⁺-induced contraction of smooth muscle. In addition, cytotoxicity testing showed that compounds 1 and 9 with α,β-unsaturated ketone exhibited inhibitory activities against a small panel of human cancer cell lines.