| Autor: |
Kagho MD; Department of Chemistry and Molecular Biology, Division of Organic and Medicinal Chemistry, University of Gothenburg, Medicinaregatan 7B, SE-413 90 Göteborg, Sweden., Schmidt K, Lambert C; Division of Molecular Cell Biology, Zoological Institute, Technische Universität Braunschweig, Spielmannstrasse 7, D-38106 Braunschweig, Germany., Kaufmann T; Institute for Biophysical Chemistry, Hannover Medical School, Carl-Neuberg Strasse 1, D-30625 Hannover, Germany., Jia L, Faix J; Institute for Biophysical Chemistry, Hannover Medical School, Carl-Neuberg Strasse 1, D-30625 Hannover, Germany., Rottner K; Division of Molecular Cell Biology, Zoological Institute, Technische Universität Braunschweig, Spielmannstrasse 7, D-38106 Braunschweig, Germany., Stadler M; Institute of Microbiology, Technische Universität Braunschweig, Spielmannstraße 7, D-38106 Braunschweig, Germany., Stradal T, Klahn P; Department of Chemistry and Molecular Biology, Division of Organic and Medicinal Chemistry, University of Gothenburg, Medicinaregatan 7B, SE-413 90 Göteborg, Sweden. |
| Abstrakt: |
In search of a more comprehensive structure-activity relationship (SAR) regarding the inhibitory effect of cytochalasin B ( 2 ) on actin polymerization, a virtual docking of 2 onto monomeric actin was conducted. This led to the identification of potentially important functional groups of 2 (i.e., the NH group of the isoindolone core (N-2) and the hydroxy groups at C-7 and C-20) involved in interactions with the residual amino acids of the binding pocket of actin. Chemical modifications of 2 at positions C-7, N-2, and C-20 led to derivatives 3 - 6 , which were analyzed for their bioactivities. Compounds 3 - 5 exhibited reduced or no cytotoxicity in murine L929 fibroblasts compared to that of 2 . Moreover, short- and long-term treatments of human osteosarcoma cells (U-2OS) with 3 - 6 affected the actin network to a variable extent, partially accompanied by the induction of multinucleation. Derivatives displaying acetylation at C-20 and N-2 were subjected to slow intracellular conversion to highly cytotoxic 2 . Together, this study highlights the importance of the hydroxy group at C-7 and the NH function at N-2 for the potency of 2 on the inhibition of actin polymerization. |
