Flavonoid dimers and tetramers from Serbian Cotinus coggygria Scop.

As part of our ongoing investigation of the Cotinus coggygria flavonoid complex, five previously undescribed compounds, namely, heterodimers of flavanonol (-)-fustin and aurone sulfuretin 6-8, named fusturetins A, B and C, respectively, and cyclobutane tetramers of sulfuretin 9 and 10, named tetrasulfuretins A and B, respectively, were isolated from the heartwood and structurally characterized using 1D and 2D NMR, HRMS, UV, ECD and IR spectroscopy. In addition, three known homodimers, bis-sulfuretins (3-5), were isolated for the first time from natural sources. Their structures were elucidated by comparison of their spectroscopic data with those of the same compounds obtained by synthesis in our laboratory via laccase-mediated dimerization of sulfuretin using the enzyme from Trametes versicolor. The linkage between fustin and sulfuretin in heterodimers 6-8, and between two sulfuretin molecules in 3-5, could be rationalized by oxidative coupling involving the sulfuretin double bond and the catechol moiety of fustin or sulfuretin, respectively. The final stage of tetramers 9 and 10 biosynthesis, formation of cyclobutane ring, was proposed to be a [2 + 2] cycloaddition of 2(10)-double bonds in 3. Cytotoxicity screening of compounds 3-10 against human cervical adenocarcinoma HeLa, breast adenocarcinoma MDA-MB-231, and myelogenous leukemia K562 cell lines, as well as normal fibroblasts MRC-5, revealed moderate activity of tetramer 9 and dimer 4 against K562 cells, with moderate selectivity.