title: Design and Synthesis of Dimeric Securinine Analogues with Neuritogenic Activities.
abstract: Neurite outgrowth is crucial during neuronal development and regeneration, and strategies that aim at promoting neuritogenesis are beneficial for reconstructing synaptic connections after neuronal degeneration and injury. Using a bivalent analogue strategy as a successful approach, the current study identifies a series of novel dimeric securinine analogues as potent neurite outgrowth enhancers. Compounds 13, 14, 17-19, and 21-23, with different lengths of carbon chain of N,N-dialkyl substituting diacid amide linker between two securinine molecules at C-15 position, exhibited notable positive effects on both neuronal differentiation and neurite extension of neuronal cells. Compound 14, one of the most active compounds, was used as a representative compound for mechanistic studies. Its action on neurite outgrowth was through phosphorylation/activation of multiple signaling molecules including Ca2+/calmodulin-dependent protein kinase II (CaMKII), extracellular signal-regulated kinase (ERK) and Akt. These findings collectively identify a new group of beneficial compounds for neuritogenesis, and may provide insights on drug discovery of neural repair and regeneration.
authors.forename: Genyun
authors.initials: G
authors.lastname: Tang
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Nan
authors.initials: N
authors.lastname: Ma
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Huang
authors.forename: Zhen-Long
authors.initials: ZL
authors.lastname: Wu
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Bing-Xin
authors.initials: BX
authors.lastname: Zhao
authors.forename: Zhen-Ya
authors.initials: ZY
authors.lastname: Wang
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience and Molecular Neuroscience Center, The Hong Kong University of Science and Technology , Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Fanny C F
authors.initials: FC
authors.lastname: Ip
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience and Molecular Neuroscience Center, The Hong Kong University of Science and Technology , Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Nancy Y
authors.initials: NY
authors.lastname: Ip
authors.forename: Wen-Cai
authors.initials: WC
authors.lastname: Ye
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Chen
mesh_terms: D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D049108:Cell Enlargement / Q000187:drug effects*; D045744:Cell Line, Tumor; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006572:Heterocyclic Compounds, Bridged-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007150:Immunohistochemistry; D007783:Lactones / Q000737:chemistry; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D015394:Molecular Structure; D016501:Neurites / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000737:chemistry; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D001381:Azepines; D006572:Heterocyclic Compounds, Bridged-Ring; D007783:Lactones; D018696:Neuroprotective Agents; D010880:Piperidines; D051057:Proto-Oncogene Proteins c-akt; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048049:Extracellular Signal-Regulated MAP Kinases; C000785:securinine
keywords: Bivalent analogue strategy; neurite; neuronal differentiation; securinine