Silvestrol and Episilvestrol, Potential Anticancer Rocaglate Derivatives from <i>Aglaia silvestris</i>

Hwang, Bang Yeon; Su, Bao Ning; Chai, Heebyung; Mi, Qiuwen; Kardono, Leonardus B.S.; Afriastini, Johar J.; Riswan, Soedarsono; Santarsiero, Bernard D.; Mesecar, Andrew D.; Wild, Robert A.; Fairchild, Craig R.; Vite, Gregory D.; Rose, William C.; Farnsworth, Norman R.; Cordell, Geoffrey A.; Pezzuto, John M.; Swanson, Steven M.; Kinghorn, A. Douglas

doi:10.1021/jo040120f

Cited by 178 publications

(199 citation statements)

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“…The isolation and characterization of silvestrol have been described previously (8). Vincristine sulfate, 2-fluoroara-A (active metabolite of fludarabine), and rhodamine 123 were purchased from Sigma-Aldrich (St. Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

“…Silvestrol is a structurally unique cyclopenta [b]benzofuran agent from the plant genus Aglaia, isolated and characterized by Kinghorn and colleagues (8). Silvestrol has nanomolar potency against multiple solid tumor cell lines, as well as in vivo efficacy in a murine P388 leukemia model (8,9).…”

Section: Introductionmentioning

confidence: 99%

“…Silvestrol has nanomolar potency against multiple solid tumor cell lines, as well as in vivo efficacy in a murine P388 leukemia model (8,9). We subsequently demonstrated that silvestrol has potent cytotoxicity against leukemic B cell lines and primary cells, shows selectivity against B cells relative to T cells, and significantly prolongs survival in a murine model of B cell acute lymphoblastic leukemia (ALL).…”

Section: Introductionmentioning

confidence: 99%

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Resistance to the Translation Initiation Inhibitor Silvestrol is Mediated by ABCB1/P-Glycoprotein Overexpression in Acute Lymphoblastic Leukemia Cells

Gupta

Sass

Davis

et al. 2011

AAPS J

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Abstract. Protein synthesis is a powerful therapeutic target in leukemias and other cancers, but few pharmacologically viable agents are available that affect this process directly. The plant-derived agent silvestrol specifically inhibits translation initiation by interfering with eIF4A/mRNA assembly with eIF4F. Silvestrol has potent in vitro and in vivo activity in multiple cancer models including acute lymphoblastic leukemia (ALL) and is under pre-clinical development by the US National Cancer Institute, but no information is available about potential mechanisms of resistance. In a separate report, we showed that intraperitoneal silvestrol is approximately 100% bioavailable systemically, although oral doses were only 1% bioavailable despite an apparent lack of metabolism. To explore mechanisms of silvestrol resistance and the possible role of efflux transporters in silvestrol disposition, we characterized multi-drug resistance transporter expression and function in a silvestrol-resistant ALL cell line generated via culture of the 697 ALL cell line in gradually increasing silvestrol concentrations. This resistant cell line, 697-R, shows significant upregulation of ABCB1 mRNA and P-glycoprotein (Pgp) as well as cross-resistance to known Pgp substrates vincristine and romidepsin. Furthermore, 697-R cells readily efflux the fluorescent Pgp substrate rhodamine 123. This effect is prevented by Pgp inhibitors verapamil and cyclosporin A, as well as siRNA to ABCB1, with concomitant re-sensitization to silvestrol. Together, these data indicate that silvestrol is a substrate of Pgp, a potential obstacle that must be considered in the development of silvestrol for oral delivery or targeting to tumors protected by Pgp overexpression.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Resistance to the Translation Initiation Inhibitor Silvestrol is Mediated by ABCB1/P-Glycoprotein Overexpression in Acute Lymphoblastic Leukemia Cells

Gupta

Sass

Davis

et al. 2011

AAPS J

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“…The vicinal coupling constant value of the methine protons at the C-1, 2, and 3 positions (J 1,2 = 5.3 Hz and J 2,3 = 13.6 Hz) were consistent with 1α, 2α, and 3β configurations, respectively, as well as a cis-B/C ring junction. 17 The NOESY correlations from H-2 to H-1, H-2′, 6′, and H-2″, 6″, from H-3 to H-2″, 6″, and from H-1 to H-2 confirmed the relative configurations of H-1, H-2 and H-3 as being β, β, and α, respectively. The absolute configuration of compound 2 was determined as 1R, 2R, 3S, 3aR, and 8bS based on comparison of its CD spectrum with other rocaglamide derivatives, 18,28 which showed a strong negative Cotton effect around 220 nm as the most characteristic feature.…”

Section: Resultsmentioning

confidence: 72%

“…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.)…”

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confidence: 99%

Cytotoxic Flavaglines and Bisamides from Aglaia edulis.

Kim¹,

Chin²,

Su³

et al. 2007

J. Nat. Prod.

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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...

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