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Bifunctional Duocarmycin Analogues as Inhibitors of Protein Tyrosine Kinases.
De Ford, Christian; Penchalaiah, Kamala; Kreft, Alexander; Humar, Matjaz; Heydenreuter, Wolfgang; Kangani, Mehrnoush; Sieber, Stephan A; Tietze, Lutz F; Merfort, Irmgard.
Afiliação
  • De Ford C; Department of Pharmaceutical Biology and Biotechnology , Albert Ludwigs University Freiburg , Stefan-Meier-Strasse 19 , D-79104 Freiburg , Germany.
  • Penchalaiah K; Spemann Graduate School of Biology and Medicine (SGBM) , Albert Ludwigs University Freiburg , Albertstrasse 19a , 79104 Freiburg , Germany.
  • Kreft A; Institute of Organic and Biomolecular Chemistry , Georg-August University , Tammannstrasse 2 , 37077 Göttingen , Germany.
  • Humar M; Institute of Organic and Biomolecular Chemistry , Georg-August University , Tammannstrasse 2 , 37077 Göttingen , Germany.
  • Heydenreuter W; Department of Pharmaceutical Biology and Biotechnology , Albert Ludwigs University Freiburg , Stefan-Meier-Strasse 19 , D-79104 Freiburg , Germany.
  • Kangani M; Institute of Organic Chemistry II , Technische Universität München , Lichtenbergstrasse 4 , 85747 Garching , Germany.
  • Sieber SA; Institute of Organic and Biomolecular Chemistry , Georg-August University , Tammannstrasse 2 , 37077 Göttingen , Germany.
  • Tietze LF; Institute of Organic Chemistry II , Technische Universität München , Lichtenbergstrasse 4 , 85747 Garching , Germany.
  • Merfort I; Institute of Organic and Biomolecular Chemistry , Georg-August University , Tammannstrasse 2 , 37077 Göttingen , Germany.
J Nat Prod ; 82(1): 16-26, 2019 01 25.
Article em En | MEDLINE | ID: mdl-30620194
Bifunctional duocarmycin analogues are highly cytotoxic compounds that have been shown to be irreversible aldehyde dehydrogenase 1 inhibitors. Interestingly, cells with low aldehyde dehydrogenase 1 expression are also sensitive to bifunctional duocarmycin analogues, suggesting the existence of another target. Through in silico approaches, including principal component analysis, structure-similarity search, and docking calculations, protein tyrosine kinases, and especially the vascular endothelial growth factor receptor 2 (VEGFR-2), were predicted as targets of bifunctional duocarmycin analogues. Biochemical validation was performed in vitro, confirming the in silico results. Structural optimization was performed to mainly target VEGFR-2, but not aldehyde dehydrogenase 1. The optimized bifunctional duocarmycin analogue was synthesized. In vitro assays revealed this bifunctional duocarmycin analogue as a strong inhibitor of VEGFR-2, with low residual aldehyde dehydrogenase 1 activity. Altogether, studies revealed bifunctional duocarmycin analogues as a new class of naturally derived compounds that express a very high cytotoxicity to cancer cells overexpressing aldehyde dehydrogenase 1 as well as VEGFR-2.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptor 2 de Fatores de Crescimento do Endotélio Vascular / Inibidores de Proteínas Quinases / Duocarmicinas Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: J Nat Prod Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Alemanha País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptor 2 de Fatores de Crescimento do Endotélio Vascular / Inibidores de Proteínas Quinases / Duocarmicinas Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: J Nat Prod Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Alemanha País de publicação: Estados Unidos