title: Design, synthesis and evaluation of multifunctional salphen derivatives for the treatment of Alzheimer's disease.
abstract: A series of salphen derivatives (1-26) have been designed, synthesized, and evaluated as chemical reagents that target and modulate multiple facets of Alzheimer's disease. Most of the compounds exhibit a significant ability to inhibit self-induced and Cu(2+)-induced β-amyloid (Aβ1-42) aggregation, and to function as potential antioxidants and biometal chelators. In particular, the antioxidant activity of compound 2 is 2.6-fold of the trolox value by using the ABTS radical scavenging method, and it also shows a significant ability to inhibit self-induced and Cu(2+)-induced β-amyloid (Aβ1-42) aggregation (70.3%, 20 μM and 85.7%, 50 μM, respectively). Moreover, it is capable of decreasing reactive oxygen species (ROS) induced by Cu(2+)-Aβ, shows a good neuroprotective effect in human SH-SY5Y neuroblastoma cells and can cross the blood-brain barrier. In addition, compound 2 retains the activities of antioxidant, anti Aβ aggregation and neuroprotection after capturing the metal ions Cu(2+), Fe(3+) and Zn(2+) (its metal complexes 18, 22 and 23). Taken together, these results suggest that compound 2 might be a promising lead compound for AD treatment.
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
authors.forename: Neng
authors.initials: N
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
authors.forename: Su-Yi
authors.initials: SY
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
authors.forename: Sai-Sai
authors.initials: SS
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
authors.forename: Zhong-Rui
authors.initials: ZR
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
authors.forename: Kelvin D G
authors.initials: KD
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China. Electronic address: xbwang@cpu.edu.cn.
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China. Electronic address: cpu_lykong@126.com.
authors.forename: Ling-Yi
authors.initials: LY
authors.lastname: Kong
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D001812:Blood-Brain Barrier; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D062105:Molecular Docking Simulation; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D010655:Phenylenediamines / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared
chemical_list: D018696:Neuroprotective Agents; D010655:Phenylenediamines; C545695:salphen
keywords: Alzheimer's disease; Antioxidant; Metal chelator; Neuroprotection; The blood–brain barrier; β-Amyloid aggregation