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

Abstract

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 [ π2 s+ π2 s] dimerization of tubastrine. The subunit head-to-tail orientation of dimer 6 was established unambiguously by interpretation of data from a 2 J, 3 J-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 IC 50s of 10–36 μM and this was associated with inhibition of superoxide production by neutrophils in vivo in a murine model of gouty inflammation.