title: Structure-activity relationship of cyclic thiacarbocyanine tau aggregation inhibitors.
abstract: Macrocyclic bis-thiacarbocyanines are efficacious inhibitors of tau protein aggregation. To extend the structure-activity relationship of this inhibitor class, N,N'-alkylene bis-thiacarbocyanines linked by chains of three to eight methylene carbons were synthesized and examined for inhibitory activity against recombinant human tau aggregation in vitro. At 10 micromolar concentration, inhibitory activity varied with linker length, with four methylene units being most efficacious. On the basis of absorbance spectroscopy measurements, linker length also affected compound folding and aggregation propensity, with a linker length of four methylene units being optimal for preserving open monomer conformation. These data suggest that inhibitory potency can be optimized through control of linker length, and that a contributory mechanism involves modulation of compound folding and aggregation.
authors.affiliation: Center for Molecular Neurobiology, Department of Molecular and Cellular Biochemistry, The Ohio State University College of Medicine, 1060 Carmack Rd, Columbus, OH 43210, USA.
authors.forename: Kelsey N
authors.initials: KN
authors.lastname: Schafer
authors.forename: Dhiraj P
authors.initials: DP
authors.lastname: Murale
authors.forename: Kibong
authors.initials: K
authors.lastname: Kim
authors.forename: Katryna
authors.initials: K
authors.lastname: Cisek
authors.forename: Jeff
authors.initials: J
authors.lastname: Kuret
authors.forename: David G
authors.initials: DG
authors.lastname: Churchill
mesh_terms: D002232:Carbocyanines / Q000737:chemistry* / Q000494:pharmacology; D003500:Cyclization; D006801:Humans; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D046912:Multiprotein Complexes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D013329:Structure-Activity Relationship; D016875:tau Proteins / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism
chemical_list: D002232:Carbocyanines; D046912:Multiprotein Complexes; D016875:tau Proteins