N-alkyl carbazole derivatives as new tools for Alzheimer's disease: preliminary studies.

Abstract

Alzheimer's disease (AD) is a progressive and age-related neurodegenerative disorder affecting brain cells and is the most common form of "dementia", because of the cognitive detriment which takes place. Neuronal disruption represents its major feature, due to the cytosolic accumulation of amyloid β-peptide (Aβ) which leads to senile plaques formation and intracellular neurofibrillary tangles. Many studies have focused on the design and therapeutic use of new molecules able to inhibit Aβ aggregation. In this context, we evaluated the ability of two recently synthesized series of N-alkyl carbazole derivatives to increase the Aβ soluble forms, through molecular docking simulations and in vitro experiments. Our data evidenced that two carbazole derivatives, the most active, adopt distinct binding modes involving key residues for Aβ fibrillization. They exhibit a good interfering activity on Aβ aggregation in mouse (N2a) cells, stably expressing wild-type human amyloid precursor protein (APP) 695. These preliminary results are promising and we are confident that the N-alkyl carbazole derivatives may encourage next future studies needed for enlarging the knowledge about the AD disease approach.

• Authors: Carmela Saturnino, Domenico Iacopetta, Maria Stefania Sinicropi, Camillo Rosano, Anna Caruso, Angelamaria Caporale, Nancy Marra, Barbara Marengo, Maria Adelaide Pronzato, Ortensia Ilaria Parisi, Pasquale Longo, Roberta Ricciarelli
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 19 Issue 7 Pg. 9307-17 (Jul 02 2014) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 24991761 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Carbazoles
• Culture Media, Conditioned
• Peptide Fragments
• Protein Aggregates
• amyloid beta-protein (1-40)
• amyloid beta-protein (1-42)

Topics

• Alzheimer Disease (drug therapy)
• Amyloid beta-Peptides (chemistry, metabolism)
• Animals
• Carbazoles (chemistry, pharmacology)
• Cell Line
• Culture Media, Conditioned
• Drug Evaluation, Preclinical
• Humans
• Mice
• Molecular Docking Simulation
• Peptide Fragments (chemistry, metabolism)
• Protein Aggregates
• Protein Aggregation, Pathological (prevention & control)
• Protein Stability
• Solubility