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Identification of Inhibitors for Mycobacterial Protein Tyrosine Phosphatase B (MptpB) by Biology‐Oriented Synthesis (BIOS) |
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| Authors: | Ivan R Corrêa Jr Dr Andrea Nören‐Müller Horst‐Dieter Ambrosi Dr Sven Jakupovic Krishna Saxena Dr Harald Schwalbe Prof Dr Markus Kaiser Dr Herbert Waldmann Prof |
| Institution: | 1. Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto‐Hahn‐Stra?e 11, D‐44367 Dortmund, Germany, and Universit?t Dortmund, Fachbereich 3, Chemische Biologie, Otto‐Hahn‐Stra?e 6, D‐44367 Dortmund, Germany, Fax: (+49)?231‐133‐3199;2. AnalytiCon Discovery, Hermannswerder Haus 17, D‐14473 Potsdam, Germany;3. Institut für Organische Chemie, Johann Wolfgang Goethe‐Universit?t, Marie‐Curie‐Stra?e 11, D‐60439 Frankfurt am Main, Germany;4. Chemical Genomics Centre of the Max Planck Society, Otto‐Hahn‐Stra?e 15, D‐44227 Dortmund, Germany;5. Zentrum für Angewandte Chemische Genomik im BioMedizinZentrum Dortmund, Otto‐Hahn‐Stra?e 15, D‐44227 Dortmund, Germany |
| Abstract: | Protein phosphatases have recently emerged as important targets for research in chemical biology and medicinal chemistry, and new classes of phosphatase inhibitors are in high demand. BIOS (biology‐oriented synthesis) employs the criteria of relevance to nature and biological prevalidation for the design and synthesis of compound collections. In an application of the BIOS principle, an efficient solid‐phase synthesis of highly substituted indolo2,3‐a]quinolizidines by using a vinylogous Mannich–Michael reaction in combination with phosgene‐ or acid‐mediated ring closure was developed. Screening of this library for phosphatase inhibitors yielded a new inhibitor class for the Mycobacterium tuberculosis phosphatase MptpB. |
| Keywords: | alkaloids biology‐oriented synthesis (BIOS) enzyme inhibition phosphatases solid‐phase synthesis |