1-carbamoylalkyl-2-phenylindoles: Relationship between side chain structure and estrrogen antagonism

Angerer, Erwin von; Biberger, Christian; Holler, Eggehard; Koop, Ronald; Leichtl, S.

doi:10.1016/0960-0760(94)90300-x

Cited by 26 publications

(6 citation statements)

References 28 publications

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“…Interestingly, well-known antiestrogen drugs, such as ICI 164,384 and 182,-780, have an alkyl side chain. The structure-activity relationship of the alkyl side chain and ER antagonism has been reported in a study in which the side chain structure was chemically modified (28).…”

Section: Discussionmentioning

confidence: 99%

Isolation and Identification of Novel Estrogenic Compounds in Yam Tuber (Dioscorea alata Cv. Tainung No. 2)

Cheng

Kuo

Huang

2007

J. Agric. Food Chem.

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Yam (Dioscorea spp.) is a common food in tropical areas and has been shown to improve the status of sex hormone in postmenopausal women. In this study, the estrogenic activity of yam was examined and active compounds were isolated and identified based on ligand-dependent transcriptional activation through estrogen receptors. Ethyl acetate extracts of various species/varieties of yam were found to activate estrogen receptors alpha and beta to various extents. The extract of Dioscorea alata cv. Tainung No. 2 tuber was fractionated by repeated silica gel column chromatography. The active compounds were isolated and purified by preparative HPLC. Based on NMR and mass spectrometry, two new compounds, hydro-Q(9) chromene (1) and gamma-tocopherol-9 (2), together with three known compounds, RRR-alpha-tocopherol (3), coenzyme Q(9) (4), and 1-feruloylglycerol (5), were identified and shown to activate human ERalpha and beta. These results provide basic evidence for the beneficial effect of yam for menopausal women.

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Section: Discussionmentioning

confidence: 99%

Isolation and Identification of Novel Estrogenic Compounds in Yam Tuber (Dioscorea alata Cv. Tainung No. 2)

Cheng

Kuo

Huang

2007

J. Agric. Food Chem.

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“…Forty-seven of the compounds contained in data set 3 were largely congeners of the 2-phenylindole prototype structure (Figures and ). − Data set 3 also included six structurally diverse estrogens: E 2 , ICI 164,384, ICI 182,780, tamoxifen, 4-hydroxytamoxifen, and hexestrol (Figures −3). The RBA values for compounds in data set 3 were obtained with calf ER.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of Quantitative Structure−Activity Relationship Methods for Large-Scale Prediction of Chemicals Binding to the Estrogen Receptor

Tong

Lowis²,

Perkins³

et al. 1998

J. Chem. Inf. Comput. Sci.

202

139

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Three different QSAR methods, Comparative Molecular Field Analysis (CoMFA), classical QSAR (utilizing the CODESSA program), and Hologram QSAR (HQSAR), are compared in terms of their potential for screening large data sets of chemicals as endocrine disrupting compounds (EDCs). While CoMFA and CODESSA (Comprehensive Descriptors for Structural and Statistical Analysis) have been commercially available for some time, HQSAR is a novel QSAR technique. HQSAR attempts to correlate molecular structure with biological activity for a series of compounds using molecular holograms constructed from counts of sub-structural molecular fragments. In addition to using r2 and q2 (cross-validated r2) in assessing the statistical quality of QSAR models, another statistical parameter was defined to be the ratio of the standard error to the activity range. The statistical quality of the QSAR models constructed using CoMFA and HQSAR techniques were comparable and were generally better than those produced with CODESSA. It is notable that only 2D-connectivity, bond and elemental atom-type information were considered in building HQSAR models. Since HQSAR requires no conformational analysis or structural alignment, it is straightforward to use and lends itself readily to the rapid screening of large numbers of compounds. Among the QSAR methods considered, HQSAR appears to offer many attractive features, such as speed, reproducibility and ease of use, which portend its utility for prioritizing large numbers of potential EDCs for subsequent toxicological testing and risk assessment.

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“…24 N-Alkylation was readily achieved by deprotonation of 1 with sodium hydride followed by the reaction with the appropriate alkyl halide. 25 The preparation of the analogous 2-phenylbenzo[b]furan 26 and 2-phenylbenzo[b]thiophene 27 has been described previously. The formyl group was introduced into the 3-position of the heterocycles by the Vilsmeier reaction using dimethylformamide and POCl 3 .…”

Section: Chemistrymentioning

confidence: 99%

Methoxy-Substituted 3-Formyl-2-phenylindoles Inhibit Tubulin Polymerization

et al. 1998

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The aim of this study was the identification of the essential structural elements in the 12-formyl-5,6-dihydroindolo[2, 1-a]isoquinoline system required for the inhibition of tubulin polymerization which is understood to be the predominant mode of action of this class of cytostatics. Since 2-phenylindole forms the main fragment of this tetracycle, it was used as the basic structure and modified with respect to the number and positions of the oxygen functions in the aromatic rings. Further modifications related to the nitrogen, which was both replaced by oxygen and sulfur and alkylated. All derivatives were tested for cytostatic activity in human breast cancer cells (MDA-MB 231, MCF-7) and inhibition of tubulin polymerization. The spectrum of activity ranged from inactive to IC50 values of 35 nM (cell growth inhibition) and 1.5 microM (tubulin polymerization), respectively, for the most active derivative 3e (3-formyl-6-methoxy-2-(4-methoxyphenyl)indole). Although the correlation between antiproliferative activity and inhibition of tubulin polymerization was not very pronounced, all of the potent cytostatic agents in this study disrupted microtubule assembly completely at the standard concentration of 40 microM. By fluorescence microscopy it was demonstrated that the derivative 3e degrades the cytoskeleton in a similar fashion as colchicine does leading to the condensation of the microtubules around the nucleus after treatment. The comparison between hydroxy and methoxy derivatives revealed a striking difference between the 2-phenylindole derivatives and the indoloisoquinolines. In the 2-phenylindole series, the methoxy compounds were much more effective than the free phenols, whereas in the tetracyclic system the effect of the hydroxy derivatives exceeded that of the methylated compounds by 1 order of magnitude. Preliminary studies on the binding mode showed that both the 2-phenylindole derivatives and the indoloisoquinolines bind to the colchicine site on tubulin.

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1-carbamoylalkyl-2-phenylindoles: Relationship between side chain structure and estrrogen antagonism

Cited by 26 publications

References 28 publications

Isolation and Identification of Novel Estrogenic Compounds in Yam Tuber (Dioscorea alata Cv. Tainung No. 2)

Isolation and Identification of Novel Estrogenic Compounds in Yam Tuber (Dioscorea alata Cv. Tainung No. 2)

Evaluation of Quantitative Structure−Activity Relationship Methods for Large-Scale Prediction of Chemicals Binding to the Estrogen Receptor

Methoxy-Substituted 3-Formyl-2-phenylindoles Inhibit Tubulin Polymerization

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