Semisynthetic neoboutomellerone derivatives as ubiquitin-proteasome pathway inhibitors |
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Authors: | Beck Joséphine Guminski Yves Long Christophe Marcourt Laurence Derguini Fadila Plisson Fabien Grondin Antonio Vandenberghe Isabelle Vispé Stéphane Brel Viviane Aussagues Yannick Ausseil Frédéric Arimondo Paola B Massiot Georges Sautel François Cantagrel Frédéric |
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Institution: | USR CNRS-Pierre Fabre No. 3388 ETaC, Centre de Recherche et Développement Pierre Fabre, 3 Avenue Hubert Curien, 31035 Toulouse Cedex 01, France. |
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Abstract: | The interesting pharmacological properties of neoboutomellerones 1 and 2 were the basis for the assembly of a small library of analogues consisting of natural products isolated from the plant Neoboutonia melleri and of semisynthetic derivatives. As the two enone systems (C23-C24a and C1-C3) and the two hydroxyls groups (C22 and C26) of neoboutomellerones are required for activity, modifications were focused on these functional groups. Biological evaluation by using a cellular assay for proteasome activity provided clues regarding the mechanism of action of these natural products and synthetic derivatives. Certain neoboutomellerone derivatives inhibited the proliferation of human WM-266-4 melanoma tumor cells at submicromolar concentration and warrant evaluation as anticancer agents. |
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