title: Synthesis, biological activity, and biopharmaceutical characterization of tacrine dimers as acetylcholinesterase inhibitors.
abstract: Tacrine (THA), as the first approved acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer's disease (AD), has been extensively investigated in last seven decades. After dimerization of THA via a 7-carbon alkyl spacer, bis(7)-tacrine (B7T) showed much potent anti-AChE activity than THA. We here report synthesis, biological evaluation and biopharmaceutical characterization of six THA dimers referable to B7T. According to IC50 values, the in vitro anti-AChE activities of THA dimers were up to 300-fold more potent and 200-fold more selective than that of THA. In addition, the anti-AChE activities of THA dimers were found to be associated with the type and length of the linkage. All studied THA dimers showed much lower cytotoxicity than B7T, but like B7T, they demonstrated much lower absorptive permeabilities than that of THA on Caco-2 monolayer model. In addition, all THA dimers demonstrated significant efflux transport (efflux ratio >4), indicating that the limited permeability could be associated with the efflux transport during absorption process. Moreover, the dimer with higher Log P value was accompanied with higher permeability but lower aqueous solubility. A balanced consideration of activity, solubility, cytotoxicity and permeability should be conducted in selection of the potential candidates for further in vivo investigation.
authors.affiliation: School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Special Administrative Region; School of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing, PR China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Qian
authors.affiliation: Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Special Administrative Region.
authors.forename: Lisi
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Applied Biology and Chemical Technology, Institute of Modern Chinese Medicine, The Hong Kong Polytechnic University, Hung Hom, Hong Kong Special Administrative Region.
authors.forename: Marvin
authors.initials: M
authors.lastname: Mak
authors.affiliation: Department of Applied Biology and Chemical Technology, Institute of Modern Chinese Medicine, The Hong Kong Polytechnic University, Hung Hom, Hong Kong Special Administrative Region.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Special Administrative Region; Department of Chemistry, South University of Science and Technology of China, Shenzhen, PR China. Electronic address: jasonhcy@sustc.edu.cn.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Ho
authors.affiliation: School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Special Administrative Region. Electronic address: joanzuo@cuhk.edu.hk.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zuo
mesh_terms: D001692:Biological Transport; D001702:Biopharmaceutics / Q000379:methods*; D018938:Caco-2 Cells; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D019281:Dimerization; D006801:Humans; D015394:Molecular Structure; D012995:Solubility; D013619:Tacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D053719:Tandem Mass Spectrometry
chemical_list: C122128:1,7-N-heptylene-bis-9,9'-amino-1,2,3,4-tetrahydroacridine; D002800:Cholinesterase Inhibitors; D013619:Tacrine
keywords: Acetylcholinesterase; Cytotoxicity; Dimers; Permeability; Tacrine