Publications by authors named "Paul J A Michiels"

5 Publications

  • Page 1 of 1

Identification of lignans and related compounds in Anthriscus sylvestris by LC-ESI-MS/MS and LC-SPE-NMR.

Phytochemistry 2011 Dec 31;72(17):2172-9. Epub 2011 Aug 31.

Department of Pharmaceutical Biology, University of Groningen, Groningen, The Netherlands.

The aryltetralin lignan deoxypodophyllotoxin is much more widespread in the plant kingdom than podophyllotoxin. The latter serves as a starting compound for the production of cytostatic drugs like etoposide. A better insight into the occurrence of deoxypodophyllotoxin combined with detailed knowledge of its biosynthestic pathway(s) may help to develop alternative sources for podophyllotoxin. Using HPLC combined with electrospray tandem mass spectrometry and NMR spectroscopy techniques, we found nine lignans and five related structures in roots of Anthriscus sylvestris (L.) Hoffm. (Apiaceae), a common wild plant in temperate regions of the world. Podophyllotoxone, deoxypodophyllotoxin, yatein, anhydropodorhizol, 1-(3'-methoxy-4',5'-methylenedioxyphenyl)1-ξ-methoxy-2-propene, and 2-butenoic acid, 2-methyl-4-[[(2Z)-2-methyl-1-oxo-2-buten-1-yl]oxy]-, (2E)-3-(7-methoxy-1,3-benzodioxol-5-yl)-2-propen-1-yl ester, (2Z)- were the major compounds. α-Peltatin, podophyllotoxin, β-peltatin, isopicropodophyllone, β-peltatin-a-methylether, (Z)-2-angeloyloxymethyl-2-butenoic acid, anthriscinol methylether, and anthriscrusin were present in lower concentrations. α-Peltatin, β-peltatin, isopicropodophyllone, podophyllotoxone, and β-peltatin-a-methylether have not been previously reported to be present in A. sylvestris. Based on our findings we propose a hypothetical biosynthetic pathway of aryltetralin lignans in A. sylvestris.
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http://dx.doi.org/10.1016/j.phytochem.2011.08.009DOI Listing
December 2011

Ligand-based NMR spectra demonstrate an additional phytoestrogen binding site for 17beta-hydroxysteroid dehydrogenase type 1.

J Steroid Biochem Mol Biol 2009 Nov 23;117(4-5):93-8. Epub 2009 Jul 23.

HWB-NMR, CR UK Institute of Cancer Sciences, University of Birmingham, Birmingham, UK.

The enzyme 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) has become an important drug target for breast cancer because it catalyzes the interconversion of estrone to the biologically more potent estradiol which also plays a crucial role in the etiology of breast cancer. Patients with an increased expression of the 17beta-HSD1 gene have a significantly worse outcome than patients without. Inhibitors for 17beta-HSD1 are therefore included in therapy development. Here we have studied binding of 17beta-HSD1 to substrates and a number of inhibitors using NMR spectroscopy. Ligand observed NMR spectra show a strong pH dependence for the phytoestrogens luteolin and apigenin but not for the natural ligands estradiol and estrone. Moreover, NMR competition experiments show that the phytoestrogens do not replace the estrogens despite their similar inhibition levels in the in vitro assay. These results strongly support an additional 17beta-HSD1 binding site for phytoestrogens which is neither the substrate nor the co-factor binding site. Docking experiments suggest the dimer interface as a possible location. An additional binding site for the phytoestrogens may open new opportunities for the design of inhibitors, not only for 17beta-HSD1, but also for other family members of the short chain dehydrogenases.
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http://dx.doi.org/10.1016/j.jsbmb.2009.07.004DOI Listing
November 2009

SALMON: solvent accessibility, ligand binding, and mapping of ligand orientation by NMR spectroscopy.

J Med Chem 2008 Jan 7;51(1):1-3. Epub 2007 Dec 7.

CR UK Institute for Cancer Studies, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 2TT, UK.

Quinone oxidoreductase 2 (NQO2) binds the prodrug tretazicar (also known as CB1954, 5-(aziridin-1-yl)-2,4-dinitrobenzamide), which exhibits a profound antitumor effect in human cancers when administered together with caricotamide. X-ray structure determination allowed for two possible orientations of the ligand. Here we describe a new NMR method, SALMON (solvent accessibility, ligand binding, and mapping of ligand orientation by NMR spectroscopy), based on waterLOGSY to determine the orientation of a ligand bound to a protein by mapping its solvent accessibility, which was used to unambiguously determine the orientation of CB1954 in NQO2.
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http://dx.doi.org/10.1021/jm701020fDOI Listing
January 2008

Surface plasmon resonance evaluation of various aminoglycoside-RNA hairpin interactions reveals low degree of selectivity.

Chembiochem 2004 Jul;5(7):937-42

Leiden Institute of Chemistry, Gorlaeus Laboratories, P. O. Box 9502, 2300 RA Leiden, The Netherlands.

Aminoglycoside antibiotics, which are able to selectively bind to RNA, are considered to be an important lead in RNA-targeting drug discovery. In this study, surface plasmon resonance (SPR) was employed to explore the interaction of aminoglycosides with known tobramycin-binding RNA hairpins (aptamers) and an unrelated RNA hairpin. It was established that aminoglycosides have multiple interactions with RNA hairpins. Unexpectedly, the different hairpins showed comparable affinity for a set of related aminoglycosides. The observed absence of selectivity presents an extra hurdle in the discovery of novel aminoglycosides as specific drugs that target defined RNA hairpins.
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http://dx.doi.org/10.1002/cbic.200300819DOI Listing
July 2004

Targeting RNA: new opportunities to address drugless targets.

Drug Discov Today 2003 Apr;8(7):297-306

N.V. Organon, Lead Discovery Unit, Oss P.O. Box 20, 5340 BH OSS, The Netherlands.

Historically, pharmaceutical industries have focussed on the discovery of compounds that target the protein products of genes. The intermediary product between gene and protein, consisting of RNA, has remained largely unexplored. Several drugs targeting the rRNA of bacteria have been, however, in clinical use for over half a century. One of these drug classes, the aminoglycoside antibiotics, also targets human rRNA, and have been developed as therapeutics for genetic disorders. Targeting at the RNA level is an economical approach to address non-drugable proteins and targets that have failed to give leads by hits in HTS, as it can build on biological knowledge gathered over years. RNA also offers entirely new opportunities for drug development, such as targeting of non-coding RNA sequences.
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http://dx.doi.org/10.1016/s1359-6446(03)02624-2DOI Listing
April 2003
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