Alzheimer’s and prion diseases etiological mechanisms have been linked to a conformational change of normally expressed proteins that leads to the aggregation and abnormal deposition of protease-resistant and insoluble isoforms, namely amyloid-beta (A-beta) and prion protein scrapie (PrPSc). As the fibrillar aggregates of both these proteins are toxic to neurons, it has long been hypothesized that fibrils cause the underlying neurodegeneration. Thus, the amyloid plaques have been historically considered the neuropathological hallmark of these diseases determined at autopsy and, more recently, the classical biomarker for diagnostic purposes. In a personalized medicine perspective, a molecular biomarker can be utilized in the diagnosis, but also in staging and monitoring of therapy. On these basis, we explored the possibility of devising imaging probes to image the amyloid deposition in vivo and potentially provide treatment strategies against both maladies. To this aim, we focused on styryl derivatives, because several styryl compounds have been employed to detect A-beta plaques and have been successfully tested against PrPSc. Since the quinoline fragment is contained in many anti-prion compounds, we proposed to generate a library of styrylquinoline derivatives, to detect, and potentially inhibit fibrillar aggregates. The synthesis of the designed derivatives was achieved via a vinylogous variation of the Povarov reaction. They exhibited a promising activity against prion replication in ScGT1 cells and, importantly, showed no appreciable cytotoxicity. We also studied their activity as inhibitors of A-beta and PrPSc aggregation in vitro. To corroborate the possibility of employing them in vivo, we tested their ability to cross the BBB and investigated their native fluorescence in a variety of polar and non-polar environments to model their interaction with proteins, and provide the information required for their possible use as theranostic agents.
Styrylquinolines as amyloid chemical probes and theranostics in Alzheimer’s and prion diseases / M. L. Bolognesi. - ELETTRONICO. - (2012), pp. 36-36. (Intervento presentato al convegno Personalised Medicine: Better Healthcare for the Future - A Rational Approach Focusing on Bioinformatics, Medicinal Chemistry and Medicine tenutosi a Larnaca nel 17 - 22 June 2012).
Styrylquinolines as amyloid chemical probes and theranostics in Alzheimer’s and prion diseases
BOLOGNESI, MARIA LAURA
2012
Abstract
Alzheimer’s and prion diseases etiological mechanisms have been linked to a conformational change of normally expressed proteins that leads to the aggregation and abnormal deposition of protease-resistant and insoluble isoforms, namely amyloid-beta (A-beta) and prion protein scrapie (PrPSc). As the fibrillar aggregates of both these proteins are toxic to neurons, it has long been hypothesized that fibrils cause the underlying neurodegeneration. Thus, the amyloid plaques have been historically considered the neuropathological hallmark of these diseases determined at autopsy and, more recently, the classical biomarker for diagnostic purposes. In a personalized medicine perspective, a molecular biomarker can be utilized in the diagnosis, but also in staging and monitoring of therapy. On these basis, we explored the possibility of devising imaging probes to image the amyloid deposition in vivo and potentially provide treatment strategies against both maladies. To this aim, we focused on styryl derivatives, because several styryl compounds have been employed to detect A-beta plaques and have been successfully tested against PrPSc. Since the quinoline fragment is contained in many anti-prion compounds, we proposed to generate a library of styrylquinoline derivatives, to detect, and potentially inhibit fibrillar aggregates. The synthesis of the designed derivatives was achieved via a vinylogous variation of the Povarov reaction. They exhibited a promising activity against prion replication in ScGT1 cells and, importantly, showed no appreciable cytotoxicity. We also studied their activity as inhibitors of A-beta and PrPSc aggregation in vitro. To corroborate the possibility of employing them in vivo, we tested their ability to cross the BBB and investigated their native fluorescence in a variety of polar and non-polar environments to model their interaction with proteins, and provide the information required for their possible use as theranostic agents.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
