Inhibition of IκB Kinase-β and Anticancer Activities of Novel Chalcone Adamantyl Arotinoids

• Published in: Journal of medicinal chemistry 2008-09, Vol.51 (17), p.5431-5440
• Main Authors: Lorenzo, Paula, Alvarez, Rosana, Ortiz, Maria A, Alvarez, Susana, Piedrafita, F. Javier, de Lera, Ángel R
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Biological and medical sciences; General aspects; Medical sciences; Pharmacology. Drug treatments
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm800285f

On the basis of the observations that chalcone 7 (MX781) and some related adamantyl arotinoids (AdArs) inhibit IκBα kinase β (IKKβ) activity, inhibit cell growth, and induce apoptosis in cancer cells, a new series of AdArs structurally related to 7 have been designed and synthesized. Modifications were intended to reduce or eliminate RAR activity, and we evaluated the effect of the novel analogues of 7 on IKKβ activity and proliferation of a variety of cancer cell lines (leukemia, Jurkat; prostate, PC-3; breast carcinomas, T47D, MDA-MB-468). Consistent with the design principles, the biological activities of these AdArs do not appear to be RAR-mediated, since most analogues are unable to activate RAR-mediated transactivation and exhibit significantly diminished antagonist activity. All compounds are capable of inducing apoptosis in Jurkat cells, as demonstrated by elevated DEVDase activity and externalization of phosphatidylserine. Several of the analogues elicit stronger growth inhibitory activity against prostate (PC-3) and breast (MDA-MB-468) carcinoma cells, which contain elevated basal IKK activity; this antiproliferative activity correlates with increased inhibition of recombinant IKKβ in vitro, suggesting that the anticancer activities of these AdArs might be related to the inhibition of IKK/NFκB signaling.