Cytotoxic Rocaglate Derivatives from Leaves of Aglaia perviridis.

Rocaglate, a class of structurally complex secondary metabolites from plants of the Aglaia genus (Meliaceae), have attracted great attentions for their considerable cytotoxicity1,2,3,4,5. Rocaglates could block cell cycle progression6,7,8,9,10,11,12,13 from G2 to M and exhibited promising activity in human tumor cell lines and xenograft models. Their cytostatic effects are comparable to those of established anticancer drugs such as vinblastine sulphate, actinomycin D, and hydroxycamptothecine14,15. Rocaglates possess cyclopenta[b]benzofuran skeleton, which originates from the [3 + 2] cyclization products of flavonol and diamide (cyclopenta[bc]benzofurans). Silvestrols, featuring an unprecedented dioxanyloxy unit attached to phenyl ring A of the cyclopenta[b]benzofuran skeleton, is a rare subtype of rocaglate, mostly of marked cytotoxicity8,11,13. The structure complexity and the potent activities of silvestrols have attracted significant interest in their biosynthesis and total synthesis16,17,18,19. In the plant kingdom, silvestrol analogues are characteristically and exclusively present in Aglaia species, and only four silvestrols have been reported4 as yet. Certain Aglaia species have been used as traditional medicines for treating fever, cough, diarrhoea, and contused wounds4,5. In continuation of the discovery of novel and bioactive natural products from plants of the Meliaceae family20,21,22, the species A. perviridis, a wild shrub indigenous to Yunnan Province of China20,21,22, was investigated to find cytotoxic rocaglates, particularly silvestrols. As a result, three silvestrol analogues including a new one (aglapervirisin A, 1), eight new biosynthetic precursors of rocaglates (cyclopenta[bc]benzopyrans, 2–9), and three known precursors (12–14) were isolated and purified from the leaves of A. perviridis (Fig. 1). Their structures were mainly elucidated through comprehensive analysis using spectroscopic methods, including IR, UV, MS, HRESIMS, 1D-NMR and 2D-NMR. The absolute configuration of 1 was determined by ECD analysis and chemical conversion, and that of 2 was established by single-crystal X-ray diffraction using Cu Kα radiation. These isolates (except for 6 and 12) were evaluated for their cytotoxicity against four human cancer cell lines: three silvestrol analogues (1, 10 and 11) showed potent activity with IC50 values between 8.0 and 15.0 nM. Of them, 1 induced cell cycle arrest by reducing the Cdc2 and Cdc25C expression levels in a dose-dependent manner and induced the apoptosis of these cells at concentrations over 160 nM. Herein, we report the separation and structural elucidation of these isolated rocaglate derivatives, as well as the bioassay results. Figure 1 Chemical structures of compounds 1–9, 1a, 10a and 11a.