title: Bimodal-hybrid heterocyclic amine targeting oxidative pathways and copper mis-regulation in Alzheimer's disease.
abstract: Oxidative stress resulting from metal-ion misregulation plays a role in the development of Alzheimer's disease (AD). This process includes the production of tissue-damaging reactive oxygen species and amyloid aggregates. Herein we describe the synthesis, characterization and protective capacity of the small molecule, lipoic cyclen, which has been designed to target molecular features of AD. This construct utilizes the biologically compatible and naturally occurring lipoic acid as a foundation for engendering low cellular toxicity in multiple cell lines, radical scavenging capacity, tuning the metal affinity of the parent cyclen, and results in an unexpected affinity for amyloid without inducing aggregation. The hybrid construct thereby shows protection against cell death induced by amyloid aggregates and copper ions. These results provide evidence for the rational design methods used to produce this fused molecule as a potential strategy for the development of lead compounds for the treatment of neurodegenerative disorders.
authors.affiliation: Department of Chemistry, Texas Christian University, 2800 S. University, Fort Worth, USA. kayla.green@tcu.edu.
authors.forename: Paulina
authors.initials: P
authors.lastname: Gonzalez
authors.forename: Viviana C P
authors.initials: VC
authors.lastname: da Costa
authors.forename: Kimberly
authors.initials: K
authors.lastname: Hyde
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wu
authors.forename: Onofrio
authors.initials: O
authors.lastname: Annunziata
authors.forename: Josep
authors.initials: J
authors.lastname: Rizo
authors.forename: Giridhar
authors.initials: G
authors.lastname: Akkaraju
authors.forename: Kayla N
authors.initials: KN
authors.lastname: Green
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000588:Amines / Q000378:metabolism*; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D003300:Copper / Q000378:metabolism*; D000080027:Cyclams; D006571:Heterocyclic Compounds / Q000378:metabolism; D006801:Humans; D051379:Mice; D008954:Models, Biological; D019906:Nuclear Magnetic Resonance, Biomolecular; D010084:Oxidation-Reduction; D008063:Thioctic Acid / Q000378:metabolism
chemical_list: D000588:Amines; D000682:Amyloid; D000080027:Cyclams; D006571:Heterocyclic Compounds; D008063:Thioctic Acid; D003300:Copper; C038072:cyclen