1. 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.
- Author
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Lallemand B, Chaix F, Bury M, Bruyère C, Ghostin J, Becker JP, Delporte C, Gelbcke M, Mathieu V, Dubois J, Prévost M, Jabin I, and Kiss R
- Subjects
- Animals, Antineoplastic Agents pharmacology, Apoptosis, Cell Line, Tumor, Cell Proliferation, Drug Resistance, Neoplasm, Drug Screening Assays, Antitumor, Glycyrrhetinic Acid pharmacology, Humans, Mice, Models, Molecular, PPAR gamma antagonists & inhibitors, Phenylurea Compounds pharmacology, Protein Kinase Inhibitors pharmacology, Structure-Activity Relationship, Antineoplastic Agents chemical synthesis, Glycyrrhetinic Acid analogs & derivatives, Glycyrrhetinic Acid chemical synthesis, Phenylurea Compounds chemical synthesis, Proteasome Inhibitors, Protein Kinase Inhibitors chemical synthesis
- 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.
- Published
- 2011
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