Orthidines A-E, tubastrine, 3,4-dimethoxyphenethyl-β-guanidine, and 1,14-sperminedihomovanillamide: potential anti-inflammatory alkaloids isolated from the New Zealand ascidian Aplidium orthium that act as inhibitors of neutrophil respiratory burst

In addition to the known dihydroxystyrylguanidine alkaloid tubastrine (1), five new dimers, orthidines A-E (2-6) and the biosynthetically unrelated 1,14-sperminedihomovanillamide (orthidine F, 7) were isolated from the New Zealand ascidian Aplidium orthium. The structures of the new compounds, elucidated by interpretation of spectroscopic data, encompass benzodioxane neolignan-type scaffolds (2-5) and a 1,2,3,4-tetrasubstituted cyclobutane (6), the latter likely having arisen via [π2s+π2s] dimerization of tubastrine. The subunit head-to-tail orientation of dimer 6 was established unambiguously by interpretation of data from a 2J,3J-HMBC NMR experiment. The structure of 7 was also confirmed by facile synthesis. Compounds 1-4, 6, and 7 inhibited the in vitro production of superoxide by PMA-stimulated human neutrophils in a dose-dependent manner with IC50s of 10-36 μM and this was associated with inhibition of superoxide production by neutrophils in vivo in a murine model of gouty inflammation.