1H-Cyclopenta[b]benzofuran Lignans from Aglaia Species Inhibit Cell Proliferation and Alter Cell Cycle Distribution in Human Monocytic Leukemia Cell Lines

Bohnenstengel, Frank; Steube, Klaus G.; Meyer, Corinna; Quentmeier, Hilmar; Nugroho, Bambang W.; Proksch, Peter

doi:10.1515/znc-1999-1212

Cited by 41 publications

(60 citation statements)

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“…40,41 Using 3 H]-thymidine incorporation to monitor the effect of Roc on DNA synthesis, several Roc compounds were shown to rapidly inhibit DNA biosynthesis in the human leukemia cell lines MONO-MAC-1 and MONO-MAC-6 at concentrations well below those of cycloheximide. 40 Concentrationdependent inhibition of BrdU incorporation into replicating DNA was also observed in two human colon carcinoma cell lines, SW480 and HT29/HI1, treated with a Roc derivative aglaiastatin. 41 Inhibition of DNA biosynthesis causes replication stress and finally stalled replication.…”

Section: Discussionmentioning

confidence: 99%

The natural anticancer compound rocaglamide selectively inhibits the G1-S-phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints

et al. 2013

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Targeting the cancer cell cycle machinery is an important strategy for cancer treatment. Cdc25A is an essential regulator of cycle progression and checkpoint response. Over-expression of Cdc25A occurs often in human cancers. In this study, we show that Rocaglamide-A (Roc-A), a natural anticancer compound isolated from the medicinal plant Aglaia, induces a rapid phosphorylation of Cdc25A and its subsequent degradation and, thereby, blocks cell cycle progression of tumor cells at the G1-S phase. Roc-A has previously been shown to inhibit tumor proliferation by blocking protein synthesis. In this study, we demonstrate that besides the translation inhibition Roc-A can induce a rapid degradation of Cdc25A by activation of the ATM/ATRChk1/Chk2 checkpoint pathway. However, Roc-A has no influence on cell cycle progression in proliferating normal T lymphocytes. Investigation of the molecular basis of tumor selectivity of Roc-A by a time-resolved microarray analysis of leukemic vs. proliferating normal T lymphocytes revealed that Roc-A activates different sets of genes in tumor cells compared with normal cells. In particular, Roc-A selectively stimulates a set of genes responsive to DNA replication stress in leukemic but not in normal T lymphocytes. These findings further support the development of Rocaglamide for antitumor therapy.In normal cells, the cell division cycle is tightly controlled. Cancer cells are characterized by deregulation in the cell division cycle, which is associated with increased DNA replication and elevated cellular proliferation. 1-3 Therefore, targeting the cancer cell cycle machinery has been considered to be a rational strategy for cancer treatment. 4 Cell division is governed by cyclin dependent kinases (CDKs) that are tightly regulated by cyclins and CDK inhibitors (CDKIs). Tumor-associated cell cycle defects often show alterations in CDK expression or/and activity. 2 Typically, CDK4 and CDK6 that are crucial for G1 checkpoint control are often over-expressed in many malignancies. 2,3 Evidence shows that deregulation of CDK4 and CDK6 activity is associated with a wide variety of tumors. 2 Moreover, elevated expressions of the cell division cycle 25 (Cdc25) phosphatases, in particular, the isoform Cdc25A, which is essential for cell cycle transitions of G1-S and S-G2, has been shown in different cancers and their over-expression often correlates with more aggressive disease and poor prognosis. 1,5 Recently, genetic studies indicate that CDK2, CDK4 and CDK6 are not essential for the mammalian cell cycle. Instead, they are only required for the proliferation of specific cell types. 2 Thus, targeting the activities of CDK2, CDK4 and CDK6 may be a promising approach for cancer treatment.Rocaglamides (Roc; 5 Flavaglines), derived from the traditional Chinese medicinal plant Aglaia, are a group of naturally occurring herbal chemicals. A number of Roc compounds have been shown to possess potent inhibitory effects on tumor growth in vitro and in vivo in animal models with IC 50 concentrations at the n...

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Section: Discussionmentioning

confidence: 99%

The natural anticancer compound rocaglamide selectively inhibits the G1-S-phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints

et al. 2013

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“…In the gas phase, two substituents of the furan ring-the carboxyl and methyl groups-adopt the cis and trans orientations, while in the solid phase only one form is present. The C=O and C-CH 3 bonds are trans for the derivatives of 2-benzo[b]furancarboxylic acid (1, 2), and cis for the derivatives of 3-benzo[b]furancarboxylic acid (3,4). The trans conformation, energetically less favorable, observed in the crystals of 1 and 2, is probably induced by intermolecular forces.…”

Section: Resultsmentioning

confidence: 99%

“…The benzofuran derivatives, isolated from natural sources as well as synthetic, show cytostatic and/or antitumor activity (e.g., [1][2][3][4][5][6][7][8][9]). Therein, neolignans isolated from the Persea species are cytotoxic in vitro to the human cancer cell lines: mouth epidermoid carcinoma, lung adenocarcinoma, and colon adenocarcinoma [7].…”

Section: Introductionmentioning

confidence: 99%

“…However, the papers on the molecular structure of relatively simple benzo [b]furan derivatives are very scarce and there is no report on the structure of any benzo [b]furan-monocarboxylic acid (see Supplementary Material). In this study, we present the conformational analysis of 7-acetyl-6-methoxy-3-methylbenzo[b]furan-2-carboxylic acid (1), 7-acetyl-5-bromo-6-hydroxy-3-methylbenzo[b]furan-2-carboxylic acid (2), 6-acetyl-5-hydroxy-2-methylbenzo[b]furan-3-carboxylic acid (3), and methyl ester of 6-acetyl-5-hydroxy-2-methylbenzo [b]furan-3-carboxylic acid (4) (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

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Derivatives of benzo[b]furan. Part II. Structural studies of derivatives of 2- and 3-benzo[b]furancarboxylic acids

et al. 2012

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The selected derivatives of the 2-and 3-benzo [b]furancarboxylic acids were synthesized and their structures were studied using the X-ray crystallography and the computational methods. The monocarboxylic acids (1-3) crystallize as dimers stabilized by the O-HÁÁÁO intermolecular hydrogen bonds. Moreover, intramolecular hydrogen bonds are formed between the OH and C(=O)CH 3 groups, substituted to the aromatic ring (2-4). In the crystal structures of 1-4, weak C-HÁÁÁO, C-HÁÁÁp, and C-HÁÁÁBr interactions stabilize the three-dimensional packing of molecules. The crystalline sodium complex of 1 has the stoichiometry [Na 1 Á1A 2 Á1B]Á1C, thus, the asymmetric unit contains three different moieties of 1. In this complex, the Na ? cation is hexacoordinated having a strongly distorted tetragonal bipyramidal polyhedron. For each molecule 1-4, several conformers were obtained in the gas phase. It was achieved by the rotations of substituents [COOR and/or C(=O)CH 3 , where R = H, CH 3 ] with respect to the rigid benzo[b]furan system. As indicated by the quantum-chemical calculations, the solid-state conformers for 3 and 4 (3-benzo[b]furancarboxylic acid derivatives) are the most stable ones. In contrast, the solidstate conformers of the 2-benzo[b]furancarboxylic acid derivatives (1, 2) have the energies higher than the lowest energy conformer by 1.23 and 0.69 kcal/mol, respectively. It seems that intermolecular contacts in the crystal influence on the orientation of substituents, and the conformers observed in the sodium complex of 1 provide evidence of such flexibility.

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“…In addition, the occurrence of unknown cytotoxic compounds was suggested with possible molecular formulas of C 29 H 28 O 9 and C 27 H 26 O 7 . Further fractionation on this extract led to the purification of six additional rocaglaol derivatives, including two new cyclopenta [b]benzofurans, 8b-Omethyl-4′-demethoxy-3′,4′-methylenedioxyrocaglaol (3) and methyl 8b-O-methyl-4′-demethoxy-3′,4′-methylenedioxyrocaglate (4), along with four rare known rocaglates, methyl 1-formyloxy-4′-demethoxy-3′,4′-methylenedioxyrocaglate (14), 7 methyl 1-formyloxyrocaglate (15), 39 8b-O-methylrocaglaol, 40 and methyl 8b-O-methylrocaglate (16). 40 The isolates were tested for their cytotoxicity against the HT-29 cancer cell line as well as the normal colon cell line, CCD-112CoN.…”

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Bioactive Flavaglines and Other Constituents Isolated from Aglaia perviridis

Li¹,

Acuña²,

Li³

et al. 2013

Planta Med

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Eight new compounds, including two cyclopenta [b]benzopyran derivatives (1, 2), two cyclopenta [b]benzofuran derivatives (3, 4), three cycloartane triterpenoids (5-7), and an apocarotenoid (8), together with 16 known compounds, were isolated from the chloroform-soluble partitions of separate methanol extracts of a combination of the fruits leaves and twigs, and of the roots of Aglaia perviridis collected in Vietnam. Isolation work was monitored using human colon cancer cells and facilitated with an LC/MS dereplication procedure. The structures of the new compounds (1-8) were determined on the basis of spectroscopic data interpretation. The Mosher ester method was employed to determine the absolute configurations of 5-7, and the absolute configurations of the 9,10-diol unit of compound 8 was established by a dimolybdenum tetraacetate [Mo 2 (AcO) 4 ] induced circular dichroism (ICD) procedure. Seven known rocaglate derivatives (9-15) exhibited significant cytotoxicity against the HT-29 cell line, with rocaglaol (9) being the most potent (ED 50 0.0007 µM). The new compounds 2-4 were also active against this cell line, with ED 50 values ranging from 0.46 to 4.7 µM. The cytotoxic compounds were evaluated against a normal colon cell line, CCD-112CoN. In addition, the new compound perviridicin B (2), three known rocaglate derivatives (9, 11, 12), as well as a known sesquiterpene, 2-oxaisodauc-5-en-12-al (17), showed significant NF-κB (p65) inhibitory activity in an ELISA assay.* Corresponding Author. Tel: +1-614-247-8094. Fax: +1-614-247-8119. kinghorn@pharmacy.ohio-state.edu. # Dedicated to Dr. Lester A. Mitscher, of the University of Kansas, for his pioneering work on the discovery of bioactive natural products and their derivatives ASSOCIATED CONTENT Supporting Information. 1 H, 13 C and 2D NMR spectra of compounds 1-8, 1 H NMR of (R)-and (S)-MTPA esters of 5-7. This material is available free-of-charge via the Internet at http://pubs.acs.org. NIH Public AccessAuthor Manuscript J Nat Prod. Author manuscript; available in PMC 2014 March 22. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptAglaia Lour., containing more than 120 species, is the largest genus of the plant family Meliaceae. 1 Aglaia species have attracted considerable interest in the area of natural products research, since they are a rich source of the "flavagline" class of bioactive agents. Flavagline derivatives have been proposed to be biogenetically derived from the coupling of a flavonoid unit and a cinnamic acid amide moiety, and can be divided into three subtypes, namely, the cyclopenta [b]benzofurans, the cyclopenta [b]benzopyrans, and the benzo [b]oxepines. [2][3][4][5] More than 100 flavaglines have been isolated from over 30 Aglaia species to date. [2][3][4][5] In a search for new anticancer agents from tropical plants, several Aglaia species, including Aglaia crassinervia, 6 A. edulis, 7 A. elliptica, 8 A. foveolata, 9-11 A. ponapensis, 12 and A. rubiginosa, 13 mainly collected from Indonesia, have been in...

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1H-Cyclopenta[b]benzofuran Lignans from Aglaia Species Inhibit Cell Proliferation and Alter Cell Cycle Distribution in Human Monocytic Leukemia Cell Lines

Cited by 41 publications

References 0 publications

The natural anticancer compound rocaglamide selectively inhibits the G1-S-phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints

The natural anticancer compound rocaglamide selectively inhibits the G1-S-phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints

Derivatives of benzo[b]furan. Part II. Structural studies of derivatives of 2- and 3-benzo[b]furancarboxylic acids

Bioactive Flavaglines and Other Constituents Isolated from Aglaia perviridis

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