Cytotoxic Flavaglines and Bisamides from Aglaia edulis.

Abstract

Two new cyclopenta [b]benzofurans, aglaroxin A 1-O-acetate (2) and 3′-methoxyaglaroxin A 1-Oacetate (3), a new benzo [b]oxepine, 19,20-dehydroedulisone A (4), and five new cyclopenta [bc]benzopyrans, edulirin A (5), edulirin A 10-O-acetate (6), 19,20-dehydroedulirin A (7), isoedulirin A (8), and isoedulirin B (9), were isolated from the bark of Aglaia edulis, along with one known cyclopenta [b]benzofuran, aglaroxin A (1). Additionally, four new amides, aglamides A-D (10-13), as well as three known compounds, aglalactone, scopoletin, and 5-hydroxy-3,6,7,4′-tetramethoxyflavone, were isolated from the leaves and/or twigs of this species. The structures of the new compounds (2-13) were elucidated by interpretation of their spectroscopic data. All isolates obtained in this study were evaluated for cytotoxicity against both several human cancer cell lines (Lu1, LNCaP, and MCF-7) and a non-tumorigenic (HUVEC) cell line. Among these isolates, the cyclopenta [b]benzofurans (1-3) exhibited potent in vitro cytotoxic activity (ED 50 range 0.001 to 0.8 μg/mL). Aglaroxin A 1-O-acetate (2) was further evaluated in the in vivo P388 lymphocytic leukemia model, by intraperitoneal injection, but found to be inactive in this model.The cyclopenta [b]benzofurans have been isolated only from the genus Aglaia (Meliaceae) and occur in two structurally related groups of compounds, the benzo [b]oxepines and cyclopenta [bc]benzopyrans. 1,2 These classes of compounds have been termed as "flavaglines" because their mutual biogenetic origin is postulated to involve a flavonoid unit linked to a cinnamic acid moiety. [3][4][5][6] Among the flavaglines, cyclopenta [b]benzofurans have received considerable recent attention as interesting lead compounds for cancer chemotherapy, [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] as a result of the cyclopenta [b]benzofuran derivative, rocaglamide from Aglaia elliptifolia, being found to exhibit antineoplastic activity in an in vivo model. 20 As a part of a National Cooperative Drug Discovery Group (NCDDG) program to discover new antitumor agents from plants, 21, 22 the leaves, twigs, and bark of Aglaia edulis (Roxb.) Wall. (Meliaceae) were separately collected in Indonesia. The chloroform-soluble partitions of the three methanol extracts of these three plant parts were subjected to detailed investigation due to their cytotoxic activities demonstrated against a small panel of human cancer cell lines. 3H, s) in the 1 H NMR spectrum suggested the presence of an acetyl group at C-1. Consistent with the 1 H NMR spectrum of compound 2, its 13 C NMR spectrum also displayed the signals for a disubstituted and a monosubstituted benzene ring, as well as for two quaternary carbons at δ C 101.0 (C-3a) and 93.3 (C-8b). In the HMBC spectrum of compound 2, correlations from H-1 and OAc to the signal at δ C 169.8 indicated the acetoxy group to be located at C-1, while correlations from resonances for H-2 and the two N-Me groups to the signal at δ C 167.5 suggested the location of the amide group at...

Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model

“…Members of this family are known to be cytotoxic (22,(24)(25)(26)(27)(28) and inhibit protein synthesis (25,29), but their molecular target(s) and mode of action are unknown. Two CBFs, 1-O-formylaglafoline (FA; also known as 1-O-formyl methyl rocaglate) and silvestrol (22) (Figure 1A), were identified and demonstrated a dose-dependent inhibition of cap-dependent firefly luciferase (FF) translation, but only a modest effect (~2-fold decrease) on HCV internal ribosome entry site-mediated (HCV IRES-mediated) translation of Renilla luciferase (Ren) in an in vitro translation assay (Figure 1, B and C; IC 50 for FF inhibition, ~4 μM and 0.3 μM for FA and silvestrol, respectively) (see Discussion for an explanation of the HCV IRES-mediated translation effect).…”

Phytochemical Profiling and Antibacterial Efficacy Screening of Aglaia Malabarica Sasidh

“…The phytochemical constituents of several other species of Aglaia have been reported earlier [8][9][10][11]. Most researches on the bioactivities of various species of Aglaia, like molluscidal, anti-inflammatory, insecticidal and antimicrobial activities have been supported with their chemical constituents [12][13][14] and this reveals the importance of the phytochemicals of this particular genus in therapeutics.…”

Comparative phytochemistry of flavaglines (= rocaglamides), a group of highly bioactive flavolignans from Aglaia species (Meliaceae)

“…Further experiments showed that it represents a potent cytotoxic agent that induces cell cycle arrest at the G 2 /M-phase and apoptosis through the mitochondrial pathway (Mi et al 2006a). Cytotoxic activities against Lu1, LNCaP and MCF-7 cells in the range of ED 50 values at 0.001 to 0.8 lg/ml were also reported for aglaroxin A (47), 1-O-acetylaglaroxin A (48), and 1-O-acetylaglaroxin B (51), all of which are characterized by a 8-methoxy-6, 7-methylenedioxy substitution of the aromatic ring A (Kim et al 2006a).…”

“…Wall. (Saifah et al 1999;Kim et al 2006a) bisamides were shown to be also linked to the rare methylthiopropenoic acid. However, to date no sulfurcontaining bisamides have been reported as part of flavaglines.…”