Inhibition of I魏B kinase-尾 and I魏B kinase-伪 by heterocyclic adamantyl arotinoids

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• 作者：Jos茅 Garc铆a-Rodr铆guez ; Santiago P茅rez-Rodr铆guez ; Mar铆a A. Ortiz ; Raquel Pereira ; Angel R. de Lera ; F. Javier Piedrafita
• 关键词：Adamantyl arotinoids ; Synthesis ; Kinase activities ; IKK
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：15 February, 2014
• 年：2014
• 卷：22
• 期：4
• 页码：1285-1302
• 全文大小：1086 K

文摘

We recently reported on a series of retinoid-related molecules containing an adamantyl group, a.k.a. adamantyl arotinoids (AdArs), that showed significant cancer cell growth inhibitory activity and activated RXR伪 (NR2B1) in transient transfection assays while devoid of RAR transactivation capacity. We have now explored whether these AdArs could also bind and inhibit IKK尾, a known target that mediates the induction of apoptosis and cancer cell growth inhibition by related AdArs containing a chalcone functional group. In addition, we have prepared and evaluated novel AdArs that incorporate a central heterocyclic ring connecting the adamantyl-phenol and the carboxylic acid at the polar termini. Our results indicate that the majority of the RXR伪 activating compounds lacked IKK尾 inhibitory activity. In contrast, the novel heterocyclic AdArs containing a thiazole or pyrazine ring linked to a benzoic acid motif were potent inhibitors of both IKK伪 and IKK尾, which in most cases paralleled significant growth inhibitory and apoptosis inducing activities.