Benzothiazole Substitution Analogs of Rhodacyanine Hsp70 Inhibitors Modulate Tau Accumulation .

Autor:	Hill SE; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States.; USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, Florida 33612, United States., Beaulieu-Abdelahad D; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States.; USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, Florida 33612, United States., Lemus A; Department of Chemistry, University of South Florida, 4202 East Fowler Avenue, CHE 205, Tampa, Florida 33620, United States., Webster JM; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States.; USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, Florida 33612, United States., Ospina SR; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States.; USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, Florida 33612, United States., Darling AL; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States.; USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, Florida 33612, United States., Martin MD; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States.; USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, Florida 33612, United States., Patel S; Department of Chemistry, University of South Florida, 4202 East Fowler Avenue, CHE 205, Tampa, Florida 33620, United States., Bridenstine L; Department of Chemistry, University of South Florida, 4202 East Fowler Avenue, CHE 205, Tampa, Florida 33620, United States., Swonger R; Department of Chemistry, University of South Florida, 4202 East Fowler Avenue, CHE 205, Tampa, Florida 33620, United States., Paul S; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States.; USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, Florida 33612, United States., Blackburn R; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States.; USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, Florida 33612, United States., Calcul L; Department of Chemistry, University of South Florida, 4202 East Fowler Avenue, CHE 205, Tampa, Florida 33620, United States., Dickey CA; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States.; USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, Florida 33612, United States.; Research Service, James A Haley Veterans Hospital, 13000 Bruce B Downs Blvd, Tampa, Florida 33612, United States., Leahy JW; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States.; Department of Chemistry, University of South Florida, 4202 East Fowler Avenue, CHE 205, Tampa, Florida 33620, United States.; Center for Drug Discovery and Innovation, University of South Florida, 3720 Spectrum Boulevard, Suite 303, Tampa, Florida 33612, United States., Blair LJ; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States.; USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, Florida 33612, United States.; Research Service, James A Haley Veterans Hospital, 13000 Bruce B Downs Blvd, Tampa, Florida 33612, United States.
Jazyk:	angličtina
Zdroj:	ACS chemical biology [ACS Chem Biol] 2023 May 19; Vol. 18 (5), pp. 1124-1135. Date of Electronic Publication: 2023 May 05.
DOI:	10.1021/acschembio.2c00919
Abstrakt:	The accumulation and aggregation of the microtubule-associated protein tau (tau) into intracellular neuronal tangles are a hallmark of a range of progressive neurodegenerative tauopathies, including Alzheimer's disease (AD), frontotemporal dementia, Pick's disease, and progressive supranuclear palsy. The aberrant phosphorylation of tau is associated with tau aggregates in AD. Members of the heat shock protein 70 kDa (Hsp70) family of chaperones bind directly to tau and modulate tau clearance and aggregation. Small molecules that inhibit the Hsp70 family of chaperones have been shown to reduce the accumulation of tau, including phosphorylated tau. Here, eight analogs of the rhodacyanine inhibitor, JG-98, were synthesized and evaluated. Like JG-98, many of the compounds inhibited ATPase activity of the cytosolic heat shock cognate 70 protein (Hsc70) and reduced total, aggregated, and phosphorylated tau accumulation in cultured cells. Three compounds, representing divergent c log P values, were evaluated for in vivo blood-brain barrier penetration and tau reduction in an ex vivo brain slice model. AL69, the compound with the lowest c log P and the lowest membrane retention in a parallel artificial membrane permeability assay (PAMPA), reduced phosphorylated tau accumulation. Our results suggest that benzothiazole substitutions of JG-98 that increase hydrophilicity may increase the efficacy of these Hsp70 inhibitors to reduce phosphorylated tau.
Databáze:	MEDLINE
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