title: Discovery of oxime-bearing naphthalene derivatives as a novel structural type of Nrf2 activators.
abstract: Recent studies have demonstrated that oxidative stress insult is one of major causes of tumor formation. Therefore, identify the effective anti-oxidative agents as a preventive approach to stop cancer progression has widely explored. Although, many potent anti-oxidative ingredients in the natural products have been identified but the amount from the nature source hindrances the clinical application. Compound which can activate Nrf2 signaling pathway result unregulated the cellular antioxidant-responses has been demonstrated as an effective chemopreventive approach for cancer treatment. In the present study, certain oxime-bearing naphthalene derivatives were synthesized and evaluated for their Nrf2 activation and anti-proliferative activities. Results indicated (E)-1-(naphthalen-2-yloxy)propan-2-one oxime (11) which increased 2.04-fold Nrf2/ARE-driven luciferase activity was more active than its 1-substituted isomer 10 (1.17-fold) and t-BHQ (1.77-fold), the known Nrf2 activator. The activities were further increased by the replacement of the peripheral methyl group with the phenyl ring in which (Z)-2-(naphthalen-2-yloxy)-1-phenylethanone oxime (13a) exhibited 3.49-fold potency of the positive control. It is worth to mention that compounds 11, 13a, and 13b which showed significant Nrf2 activation are non-cytotoxic to the tested cells with IC50>50μM. This observation strongly suggested that these compounds can be used for chemoprevention. Mechanism studies indicated that these compounds were capable of inducing the phosphorylation of Nrf2 protein at serine 40 which led to the activation of the Nrf2 transcriptional activity.
authors.affiliation: School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ken-Ming
authors.initials: KM
authors.lastname: Chang
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan.
authors.forename: Fong-Pin
authors.initials: FP
authors.lastname: Liang
authors.affiliation: Department of Pharmacy, Tajen University, Pingtung, Taiwan.
authors.forename: I-Li
authors.initials: IL
authors.lastname: Chen
authors.affiliation: School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Shyh-Chyun
authors.initials: SC
authors.lastname: Yang
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan; Department of Pediatrics, Children's Hospital, China Medical University, Taichung, Taiwan.
authors.forename: Shin-Hun
authors.initials: SH
authors.lastname: Juang
authors.affiliation: Department of Pharmacy, Tajen University, Pingtung, Taiwan.
authors.forename: Tai-Chi
authors.initials: TC
authors.lastname: Wang
authors.affiliation: Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan; Research Center for Natural Products & Drug Development, Kaohsiung Medical University, Kaohsiung City 807, Taiwan.
authors.forename: Yeh-Long
authors.initials: YL
authors.lastname: Chen
authors.affiliation: School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan; Research Center for Natural Products & Drug Development, Kaohsiung Medical University, Kaohsiung City 807, Taiwan. Electronic address: tzengch@kmu.edu.tw.
authors.forename: Cherng-Chyi
authors.initials: CC
authors.lastname: Tzeng
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D055808:Drug Discovery; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051267:NF-E2-Related Factor 2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D009281:Naphthalenes / Q000138:chemical synthesis / Q000494:pharmacology*; D018384:Oxidative Stress; D010091:Oximes / Q000138:chemical synthesis / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009281:Naphthalenes; D010091:Oximes; D006861:Hydrogen Peroxide
keywords: Antiproliferative activities; Chemoprevention; Nrf2 activation; Oxime-bearing naphthalene derivatives