Inhibition of IκB kinase-β and IκB kinase-α by heterocyclic adamantyl arotinoids.
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 RXRα (NR2B1) in transient transfection assays while devoid of RAR transactivation capacity. We have now explored whether these AdArs could also bind and inhibit IKKβ, 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 RXRα activating compounds lacked IKKβ 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 IKKα and IKKβ, which in most cases paralleled significant growth inhibitory and apoptosis inducing activities.
Departamento de Química Orgánica, CINBIO and Instituto de Investigación Biomédica de Vigo (IBIV), Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo, Spain.
José
J
García-Rodríguez
Departamento de Química Orgánica, CINBIO and Instituto de Investigación Biomédica de Vigo (IBIV), Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo, Spain.
Santiago
S
Pérez-Rodríguez
Torrey Pines Institute for Molecular Studies, 3550 General Atomics Ct, San Diego, CA 92121, USA.
María A
MA
Ortiz
Departamento de Química Orgánica, CINBIO and Instituto de Investigación Biomédica de Vigo (IBIV), Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo, Spain.
Raquel
R
Pereira
Departamento de Química Orgánica, CINBIO and Instituto de Investigación Biomédica de Vigo (IBIV), Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo, Spain. Electronic address: qolera@uvigo.es.
Angel R
AR
de Lera
Torrey Pines Institute for Molecular Studies, 3550 General Atomics Ct, San Diego, CA 92121, USA. Electronic address: jpiedrafita@tpims.org.
F Javier
FJ
Piedrafita
D000218:Adamantane / Q000737:chemistry*; D002470:Cell Survival / Q000187:drug effects; D002599:Chalcone / Q000737:chemistry; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019169:Jurkat Cells; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D047488:Retinoid X Receptors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D012176:Retinoids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; D002599:Chalcone; D051550:I-kappa B Kinase; D000218:Adamantane
Adamantyl arotinoids; IKK; Kinase activities; Synthesis