Universität zu Köln

Stein, Jan, Stahn, Sonja, Neudoerfl, Joerg-M., Sperlich, Julia, Schmalz, Hans-Guenther ORCID: 0000-0003-0489-1827 and Teusch, Nicole ORCID: 0000-0002-9030-1493 (2018). Synthetic Indolactam V Analogues as Inhibitors of PAR2-Induced Calcium Mobilization in Triple-Negative Breast Cancer Cells. ChemMedChem, 13 (2). S. 147 - 155. WEINHEIM: WILEY-V C H VERLAG GMBH. ISSN 1860-7187

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Abstract

Human proteinase-activated receptor2 (PAR2), a transmembrane G-protein-coupled receptor (GPCR), is an attractive target for a novel anticancer therapy, as it plays a critical role in cell migration and invasion. Selective PAR2 inhibitors therefore have potential as anti-metastatic drugs. Knowing that the natural product teleocidin A2 is able to inhibit PAR2 in tumor cells, the goal of the present study was to elaborate structure-activity relationships and to identify potent PAR2 inhibitors with lower activity against the adverse target, protein kinaseC (PKC). For this purpose, an efficient gram-scale total synthesis of indolactamV (i.e., the parent structure of all teleocidins) was developed, and a library of derivatives was prepared. Some compounds were indeed found to exhibit high potency as PAR2 inhibitors at low nanomolar concentrations with improved selectivity (relative to teleocidin A2). The pseudopeptidic fragment bridging the C3 and C4 positions of the indole core proved to be essential for target binding, whereas activity and target selectivity depends on the substituents at N1 or C7. This study revealed novel derivatives that show high efficacy in PAR2 antagonism combined with increased selectivity.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Stein, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Stahn, Sonja UNSPECIFIED UNSPECIFIED UNSPECIFIED Neudoerfl, Joerg-M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sperlich, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmalz, Hans-Guenther UNSPECIFIED orcid.org/0000-0003-0489-1827 UNSPECIFIED Teusch, Nicole UNSPECIFIED orcid.org/0000-0002-9030-1493 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-198589
DOI:	10.1002/cmdc.201700640
Journal or Publication Title:	ChemMedChem
Volume:	13
Number:	2
Page Range:	S. 147 - 155
Date:	2018
Publisher:	WILEY-V C H VERLAG GMBH
Place of Publication:	WEINHEIM
ISSN:	1860-7187
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Organic Chemistry
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language LYNGBYATOXIN-A TELEOCIDIN-A-1; RECEPTOR 2 PAR2; TUMOR PROMOTERS; BIOLOGICAL EVALUATION; (-)-INDOLACTAM V; ORGANIC HALIDES; ARYL HALIDES; BIOSYNTHESIS; EFFICIENT; CARBONYLATION Multiple languages Chemistry, Medicinal; Pharmacology & Pharmacy Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/19858