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Bioorg Med Chem. 2015 Aug 1;23(15):4688-98. doi: 10.1016/j.bmc.2015.05.050. Epub 2015 Jun 3.

NO-donor thiacarbocyanines as multifunctional agents for Alzheimer's disease.

Author information

1
Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, via Pietro Giuria 9, 10125 Torino, Italy.
2
Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, via Pietro Giuria 9, 10125 Torino, Italy. Electronic address: roberta.fruttero@unito.it.
3
Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
4
Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Milano, Italy.
5
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy.
6
Institute of Human Physiology, UniversitàCattolica, Roma, Italy.

Abstract

Some symmetrical and unsymmetrical thiacarbocyanines bearing NO-donor nitrooxy and furoxan moieties were synthesized and studied as candidate anti-Alzheimer's drugs. All products activated soluble guanylate cyclase (sGC) in a dose-dependent manner, depending on the presence in their structures of NO-donor groups. None displayed toxicity when tested at concentrations below 10 μM on human brain microvascular endothelial cells (hCMEC/D3). Some products were capable of inhibiting amyloid β-protein (Aβ) aggregation, with a potency in the low μM concentration range, and of inhibiting aggregation of human recombinant tau protein in amyloid fibrils when incubated with the protein at 1 μM concentration. Nitrooxy derivative 21 and furoxan derivative 22 were selected to investigate synaptic plasticity. Both products, tested at 2 μM concentration, counteracted the inhibition of long-term potentiation (LTP) induced by Aβ42 in hippocampal brain slices.

KEYWORDS:

Alzheimer disease; Long term potentiation; Nitric oxide; Tau proteins; Thiacarbocyanines; β-Amyloid

PMID:
26078011
DOI:
10.1016/j.bmc.2015.05.050
[Indexed for MEDLINE]
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