Dual inhibitors of the pro-survival proteins Bcl-2 and Mcl-1 derived from natural compound meiogynin A

• Published in: European journal of medicinal chemistry Vol. 148; pp. 26 - 38
• Main Authors: Abou Samra, Alma, Robert, Aude, Gov, Crystal, Favre, Loëtitia, Eloy, Laure, Jacquet, Eric, Bignon, Jérôme, Wiels, Joëlle, Desrat, Sandy, Roussi, Fanny
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 25.03.2018; Elsevier
• Subjects: Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - antagonists & inhibitors; B-Lymphocytes - drug effects; Bcl-2 proteins; bcl-X Protein; Cancer; Cell Line, Tumor; Chemistry, Medicinal; Fluorescence Polarization Immunoassay; Humans; Life Sciences; Life Sciences & Biomedicine; Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors; Natural compound; Pharmacology & Pharmacy; Prodrugs - chemistry; Prodrugs - pharmacology; Protein-protein interactions; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Science & Technology; Sesquiterpenes - chemistry; Structure-Activity Relationship; Bcl-2 proteins; Natural compound; Protein-protein interactions; Apoptosis; Cancer; DISCOVERY; CHEMOTHERAPY; SMALL-MOLECULE INHIBITOR; FAMILY; POTENT; X-L; MALIGNANCIES; XL/BAK; STRUCTURE-BASED DESIGN
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.01.100

Thirty analogues of natural meiogynin A, a pan-Bcl-2 inhibitor, were prepared in order to elaborate cytotoxic compounds on specific cancer cells overexpressing one or more proteins of the Bcl-2 family. The interaction of all the new analogues with Bcl-xL, Mcl-1 and Bcl-2 proteins was first evaluated by fluorescence polarization assay (FPA) and showed that modulation of the lateral chain has a dramatic impact as subtle changes significantly modify the activity on the target proteins. The acetoxymethyl prodrugs of the two most active compounds were then elaborated to determine their cytotoxicity on B cell lines. A strong cytotoxic effect on BL2, RS4;11 and H929 cells was observed with a triazole prodrug that induces apoptosis. [Display omitted]