title: Investigation on the influence of (Z)-3-(2-(3-chlorophenyl)hydrazono)-5,6-dihydroxyindolin-2-one (PT2) on β-amyloid(1-40) aggregation and toxicity.
abstract: In Alzheimer's disease (AD), native Aβ protein monomers aggregate through the formation of a variety of water-soluble, toxic oligomers, ultimately leading to insoluble fibrillar deposits. The inhibition of oligomers formation and/or their dissociation into non-toxic monomers, are considered an attractive strategy for the prevention and treatment of AD. A number of studies have demonstrated that small molecules, containing single or multiple (hetero)aromatic rings, can inhibit protein aggregation, being potentially effective in AD treatment. Starting from previously reported data on the antiamyloidogenic activity of a series of 3-hydrazonoindolinones, compound PT2 was selected to deeply investigate the inhibitory mechanism in the Aβ aggregation cascade. We compared data from DLS, NMR, CD, TEM and ThT fluorescence measures to ascertain the interactions with amyloidogenic species formed in vitro during the aggregation process, and confirmed this feature with cell viability tests on HeLa cultured cells. PT2 was effective in disrupting toxic oligomers and mature amyloid fibrils, stabilizing Aβ as non-toxic, β-sheet arranged, ThT-insensitive protofilaments. It also strongly reduced cellular toxicity caused by Aβ and showed good antioxidant properties in two radical scavenging tests. Taken together, these data confirmed that PT2 is a small molecule inhibitor of Aβ oligomerization and toxicity, displaying also additional activity as antioxidant.
authors: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via E. Orabona 4, I-70125 Bari, Italy.
authors: Marco
authors: M
authors: Catto
authors: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via E. Orabona 4, I-70125 Bari, Italy.
authors: Fabio
authors: F
authors: Arnesano
authors: Dipartimento di Chimica, Università degli Studi di Bari "Aldo Moro", via E. Orabona 4, I-70125 Bari, Italy.
authors: Gerardo
authors: G
authors: Palazzo
authors: Istituto di Virologia Vegetale del CNR, Università degli Studi di Bari "Aldo Moro", Via Amendola 165/A, I-70126 Bari, Italy.
authors: Angelo
authors: A
authors: De Stradis
authors: Dipartimento di Chimica, Università degli Studi di Bari "Aldo Moro", via E. Orabona 4, I-70125 Bari, Italy.
authors: Vincenza
authors: V
authors: Calò
authors: Dipartimento di Chimica, Università degli Studi di Bari "Aldo Moro", via E. Orabona 4, I-70125 Bari, Italy.
authors: Maurizio
authors: M
authors: Losacco
authors: Taub Institute of Columbia University, 630W 168th Street, Building P&S 12-502, New York, NY 10032, United States.
authors: Rosa
authors: R
authors: Purgatorio
authors: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via E. Orabona 4, I-70125 Bari, Italy. Electronic address: francesco.campagna@uniba.it.
authors: Francesco
authors: F
authors: Campagna
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D016166:Free Radical Scavengers / Q000378:metabolism / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D055503:Protein Multimerization / Q000187:drug effects*; D017433:Protein Structure, Secondary / Q000187:drug effects
chemical_list: C000592816:(Z)-3-(2-(3-chlorophenyl)hydrazono)-5,6-dihydroxyindolin-2-one; D016229:Amyloid beta-Peptides; D016166:Free Radical Scavengers; D007211:Indoles; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)
keywords: Alzheimer’s disease; Dynamic light scattering; Heteronuclear single quantum coherence NMR; Indolin-2-ones; Multi-target activity; β-Amyloid aggregation inhibitors