title: N-(2-{3-[3,5-bis(trifluoromethyl)phenyl]ureido}ethyl)-glycyrrhetinamide (6b): a novel anticancer glycyrrhetinic acid derivative that targets the proteasome and displays anti-kinase activity.
abstract: 18-β-Glycyrrhetinic acid (GA; 1) and many of its derivatives are cytotoxic in cancer cells. The current study aims to characterize the anticancer effects of 17 novel 1 derivatives. On the basis of these studies, N-(2-{3-[3,5-bis(trifluoromethyl)phenyl]ureido}ethyl)-glycyrrhetinamide (6b) appeared to be the most potent compound, with IC(50)in vitro growth inhibitory concentrations in single-digit micromolarity in a panel of 8 cancer cell lines. Compound 6b is cytostatic and displays similar efficiency in apoptosis-sensitive versus apoptosis-resistant cancer cell lines through, at least partly, the inhibition of the activity of a cluster of a dozen kinases that are implicated in cancer cell proliferation and in the control of the actin cytoskeleton organization. Compound 6b also inhibits the activity of the 3 proteolytic units of the proteasome. Compound 6b thus represents an interesting hit from which future compounds could be derived to improve chemotherapeutic regimens that aim to combat cancers associated with poor prognoses.
authors: Laboratoire de Chimie Bioanalytique, Toxicologie et Chimie Physique Appliquée, Faculté de Pharmacie, Université Libre de Bruxelles (ULB) , Brussels, Belgium.
authors: Benjamin
authors: B
authors: Lallemand
authors: Fabien
authors: F
authors: Chaix
authors: Marina
authors: M
authors: Bury
authors: Céline
authors: C
authors: Bruyère
authors: Jean
authors: J
authors: Ghostin
authors: Jean-Paul
authors: JP
authors: Becker
authors: Cédric
authors: C
authors: Delporte
authors: Michel
authors: M
authors: Gelbcke
authors: Véronique
authors: V
authors: Mathieu
authors: Jacques
authors: J
authors: Dubois
authors: Martine
authors: M
authors: Prévost
authors: Ivan
authors: I
authors: Jabin
authors: Robert
authors: R
authors: Kiss
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D047495:PPAR gamma / Q000037:antagonists & inhibitors; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D061988:Proteasome Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; C568507:N-(2-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)ethyl)glycyrrhetinamide; D047495:PPAR gamma; D010671:Phenylurea Compounds; D061988:Proteasome Inhibitors; D047428:Protein Kinase Inhibitors; D006034:Glycyrrhetinic Acid