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Publikation

Bobach, C.; Tennstedt, S.; Palberg, K.; Denkert, A.; Brandt, W.; de Meijere, A.; Seliger, B.; Wessjohann, L. A.; Screening of synthetic and natural product databases: Identification of novel androgens and antiandrogens Eur. J. Med. Chem. 90, 267-279, (2015) DOI: 10.1016/j.ejmech.2014.11.026

The androgen receptor is an important pharmaceutical target for a variety of diseases. This paper presents an in silico/in vitro screening procedure to identify new androgen receptor ligands. The two-step virtual screening procedure uses a three-dimensional pharmacophore model and a docking/scoring routine. About 39,000 filtered compounds were docked with PLANTS and scored by Chemplp. Subsequent to virtual screening, 94 compounds, including 28 steroidal and 66 nonsteroidal compounds, were tested by an androgen receptor fluorescence polarization ligand displacement assay. As a result, 30 compounds were identified that show a relative binding affinity of more than 50% in comparison to 100 nM dihydrotestosterone and were classified as androgen receptor binders. For 11 androgen receptor binders of interest IC50 and Ki values were determined. The compound with the highest affinity exhibits a Ki value of 10.8 nM. Subsequent testing of the 11 compounds in a PC-3 and LNCaP multi readout proliferation assay provides insights into the potential mode of action. Further steroid receptor ligand displacement assays and docking studies on estrogen receptors α and β, glucocorticoid receptor, and progesterone receptor gave information about the specificity of the 11 most active compounds.
Publikation

Bobach, C.; Schurwanz, J.; Franke, K.; Denkert, A.; Sung, T. V.; Kuster, R.; Mutiso, P. C.; Seliger, B.; Wessjohann, L. A.; Multiple readout assay for hormonal (androgenic and antiandrogenic) and cytotoxic activity of plant and fungal extracts based on differential prostate cancer cell line behavior J. Ethnopharmacol. 155, 721-730, (2014) DOI: 10.1016/j.jep.2014.06.008

Ethnopharmacological relevanceProstate cancer is one of the most diagnosed forms of cancer among men in western regions. Many traditional applications or phytotherapeutic concepts propose to inhibit the proliferation of prostate cancer cells. In order to detect influences of plant or fungal extracts and derived fractions on androgen receptor signaling pathways, a differentiating cell proliferation assay was established, which enables the simultaneous detection of hormonal and cytotoxic effects.Material and methodsThe well characterized prostate cancer cell lines LNCaP and PC-3 were used in a multiple readout assay. In all, 186 fractions of 23 traditionally used organisms were screened regarding their effects on proliferation of the two prostate cancer cell lines. The fractions were prepared by accelerated solvent extraction followed by gradient extrography. Extracts of the potential hormonally active plants Cibotium barometz, Heteropterys chrysophylla, and Sideroxylon obtusifolium (= Bumelia sartorum) were phytochemically investigated.ResultsFractions from Cibotium barometz, Cortinarius rubellus, Cyrtomium falcatum, Heteropterys chrysophylla, Nephrolepis exaltata, Salvia miltiorrhiza, Sideroxylon obtusifolium, Trichilia emetica, and Trimeria grandifolia exhibited hormonal influences on prostate cancer cells. Cytotoxic activity towards human cell lines was detected for the first time for fractions from Aglaia spectabilis (A. gigantea), Nephrolepis exaltata and Cortinarius brunneus.ConclusionsThe differential behavior of the two prostate cancer cell lines allows the discrimination between potential androgenic or antiandrogenic activities and effects on the estrogen or glucocorticoid receptor as well as cytotoxic activities. The combined cell lines assay can help to assess the biological activities of material used in traditional medicine.
Publikation

Ali, N. A. A.; Wurster, M.; Denkert, A.; Al-Sokari, S. S.; Lindequist, U.; Wessjohann, L.; Cytotoxic and antiphytofungal activity of the essential oils from two artemisia species World J. Pharm. Res. 3, 1350-1354, (2014)

Hydrodistilled essential oils from aerial parts of Artemisia abyssinica Sch.Bip. ex A. Rich, and Artemisia arborescens L. growing in Yemen were screened for their cytotoxic and antiphytofungal properties as well as their chemical compositions. Twenty-seven components were identified in the essential oils and the main components of these species were found to be davanone (42.34%), camphor (22.88%), nerolidol (8.96%), and chamazulene (4.46%), from A. abyssinica oil and artemisia ketone (51.05%), camphor (14.09%), α-bisabolol (12.56%) and α-phellandrene (8.69%) from A. arborescens. At concentration of 50 and 25 μg/mL, A. arborescens oil showed a strong cytotoxic activity with growth inhibition of 95%(±1.6) and 74%(±3.8) (IC50 of 16.91 μg/mL) against HT29 tumor cells (Human colonic adenocarcinoma cells), while A. abyssinica oil exhibited at concentration of 100 and 50 μg/mL growth inhibition of 71.0% (±12.5) and 27.3%(±14.4) (IC50 of 75.42 μg/mL) respectively. Bioautographic assay was used to evaluate the antiphytofungal activity of the oils against Cladosporium cucumerinum.
Publikation

Pando, O.; Stark, S.; Denkert, A.; Porzel, A.; Preusentanz, R.; Wessjohann, L. A.; The Multiple Multicomponent Approach to Natural Product Mimics: Tubugis, N-Substituted Anticancer Peptides with Picomolar Activity J. Am. Chem. Soc. 133, 7692-7695, (2011) DOI: 10.1021/ja2022027

The synthesis of a new generation of highly cytotoxic tubulysin analogues (i.e., tubugis) is described. In the key step, the rare, unstable, and synthetically difficult to introduce tertiary amide–N,O-acetal moiety required for high potency in natural tubulysins is replaced by a dipeptoid element formed in an Ugi four-component reaction. Two of the four components required are themselves produced by other multicomponent reactions (MCRs). Thus, the tubugis represent the first examples of the synthesis of natural-product-inspired compounds using three intertwined isonitrile MCRs.
Publikation

Shabaan, S.; Ba, L. A.; Abbas, M.; Burkholz, T.; Denkert, A.; Gohr, A.; Wessjohann, L. A.; Sasse, F.; Weber, W.; Jacob, C.; Multicomponent reactions for the synthesis of multifunctional agents with activity against cancer cells Chem. Commun. 4702, (2009) DOI: 10.1039/B823149D

Multicomponent Passerini and Ugi reactions enable the fast and efficient synthesis of redox-active multifunctional selenium and tellurium compounds, of which some show considerable cytotoxicity against specific cancer cells.

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