1,4-Benzodioxane Lignans: An Efficient, Asymmetric Synthesis of Flavonolignans and Study of Neolignan Cytotoxicity and Antiviral Profiles.

1,4-Benzodioxane lignans are a class of bioactive compounds that have received much attention through the years. Herein research pertaining to both 1,4-benzodioxane flavonolignans and 1,4-benzodioxane neolignans is presented. A novel synthesis of both traditional 1,4-benzodioxane flavonolignans and 3-deoxyflavonolignans is described. The antiviral and cytotoxic activities of 1,4-benzodioxane neolignans were then investigated; eusiderins A, B, G, and M, deallyl eusiderin A, and nitidanin, which contain the 1,4-benzodioxane motif but lack the chromanone motif found in the known antiviral flavonolignans, were tested. Notably, it was found that all eusiderin 1,4-benzodioxane neolignans exhibited greater antiviral activity than the potent and well-known silybin flavonolignans. While most modifications of the C-1' side chain did not significantly alter the cytotoxicity or antiviral activity, eusiderin M and nitidanin, which contain an allylic alcohol side chain, had lower cytotoxicity. All the eusiderins had similar antiviral activities, with eusiderin B having the best selectivity index. These results show that the chromanone moiety of the flavonolignans is not essential for bioactivity.