title: Design, synthesis and biological evaluation of regioisomers of 666-15 as inhibitors of CREB-mediated gene transcription.
abstract: cAMP-response element binding protein (CREB) is a nuclear transcription factor that has been implicated in the pathogenesis and maintenance of various types of human cancers. Identification of small molecule inhibitors of CREB-mediated gene transcription has been pursued as a novel strategy for developing cancer therapeutics. We recently discovered a potent and cell-permeable CREB inhibitor called 666-15. 666-15 is a bisnaphthamide and has been shown to possess efficacious anti-breast cancer activity without toxicity in vivo. In this study, we designed and synthesized a series of analogs of 666-15 to probe the importance of regiochemistry in naphthalene ring B. Biological evaluations of these analogs demonstrated that the substitution pattern of the alkoxy and carboxamide in naphthalene ring B is very critical for maintaining potent CREB inhibition activity, suggesting that the unique bioactive conformation accessible in 666-15 is critically important.
authors.affiliation: Program in Chemical Biology, Department of Physiology and Pharmacology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.
authors.forename: Fuchun
authors.initials: F
authors.lastname: Xie
authors.affiliation: Program in Chemical Biology, Department of Physiology and Pharmacology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.
authors.forename: Bingbing X
authors.initials: BX
authors.lastname: Li
authors.affiliation: Program in Chemical Biology, Department of Physiology and Pharmacology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA; Knight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA; Knight Cardiovascular Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA. Electronic address: xiaoxi@ohsu.edu.
authors.forename: Xiangshu
authors.initials: X
authors.lastname: Xiao
mesh_terms: D000813:Anilides / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors* / Q000502:physiology; D015195:Drug Design; D006801:Humans; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology
chemical_list: C000621942:666-15 compound; D000813:Anilides; D017362:Cyclic AMP Response Element-Binding Protein; D009281:Naphthalenes
keywords: 666-15; Bioactive conformation; CREB; Cancer; Regioisomer