Structure-Based Design of a Lead Compound Derived from Natural Schweinfurthins with Antitumor Properties That Target Oxysterol-Binding Protein.

Autor: Jézéquel G; Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, 91198 Gif-sur-Yvette, France., Rampal C; Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, 91198 Gif-sur-Yvette, France., Guimard C; Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, 91198 Gif-sur-Yvette, France., Kovacs D; Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, 91198 Gif-sur-Yvette, France., Polidori J; Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275, 06560 Valbonne, France., Bigay J; Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275, 06560 Valbonne, France., Bignon J; Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, 91198 Gif-sur-Yvette, France., Askenatzis L; Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, 91198 Gif-sur-Yvette, France., Litaudon M; Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, 91198 Gif-sur-Yvette, France., Pham VC; Institute of Marine Biochemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Caugiay, 10000 Hanoi, Vietnam., Huong DTM; Institute of Marine Biochemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Caugiay, 10000 Hanoi, Vietnam., Nguyen AL; CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), Université Paris Saclay, SPI, 91191 Gif-sur-Yvette, France., Pruvost A; CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), Université Paris Saclay, SPI, 91191 Gif-sur-Yvette, France., Virolle T; Université Côte d'Azur, CNRS, Inserm, Institut de Biologie Valrose, U1091, UMR7277, Parc Valrose, 06000 Nice,France., Mesmin B; Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275, 06560 Valbonne, France., Desrat S; Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, 91198 Gif-sur-Yvette, France., Antonny B; Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275, 06560 Valbonne, France., Roussi F; Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, 91198 Gif-sur-Yvette, France.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2023 Oct 26; Vol. 66 (20), pp. 14208-14220. Date of Electronic Publication: 2023 Oct 05.
DOI: 10.1021/acs.jmedchem.3c01298
Abstrakt: Schweinfurthins (SWs) are naturally occurring prenylated stilbenes with promising anticancer properties. They act through a novel mechanism of action similar to that of other families of natural compounds. Their known target, oxysterol-binding protein (OSBP), plays a crucial role in controlling the intracellular distribution of cholesterol. We synthesized 15 analogues of SWs and demonstrated for the first time that their cytotoxicity as well as that of natural derivatives correlates with their affinity for OSBP. Through this extensive SAR study, we selected one synthetic analogue obtained in one step from SW-G. Using its fluorescence properties, we showed that this compound recapitulates the effect of natural SW-G in cells and confirmed that it leads to cell death via the same mechanism. Finally, after pilot PK experiments, we provided the first evidence of its in vivo efficacy in combination with temozolomide in a patient-derived glioblastoma xenograft model.
Databáze: MEDLINE
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