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L-Dopa and dopamine conjugated naphthalenediimides modulate amyloid β toxicity

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Abstract

The process of protein misfolding and aggregation to form neurotoxic species is strongly implicated in most of the neurodegenerative disorders. In particular, amyloid beta (Aβ) misfolding and aggregation is central to pathophysiological processes of Alzheimer's disease. The development of aggregation modulators has enormous implications in the discovery of effective therapeutic agents for Alzheimer's disease. Herein, we report the design and synthesis of a series of natural amino acid, L-dopa and dopamine appended derivatives of naphthalenediimide (NDI) to identify efficient aggregation modulators. Furthermore, the molecular docking studies revealed the possible binding sites and binding mode of NDI-conjugates to Aβ aggregates. Among the designed NDI-conjugates, L-dopa and dopamine derivatives (NLD and NDP, respectively) showed excellent aggregation modulation efficiency (inhibition and dissolution), as shown by the thioflavin T (ThT) binding assays, dot blot analysis and in cellulo studies. The docking results from in silico studies are in good agreement with the experimental data. In addition to their significant modulation efficiency towards Aβ aggregation, NLD and NDP possess antioxidant activity conducive to the development of disease-modifying therapeutic agents for the treatment of Alzheimer's disease.

Graphical abstract: l-Dopa and dopamine conjugated naphthalenediimides modulate amyloid β toxicity

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Publication details

The article was received on 16 Jul 2018, accepted on 26 Sep 2018 and first published on 28 Sep 2018


Article type: Paper
DOI: 10.1039/C8OB01691G
Citation: Org. Biomol. Chem., 2018, Advance Article
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    L-Dopa and dopamine conjugated naphthalenediimides modulate amyloid β toxicity

    M. Ramesh, P. Makam, C. Voshavar, H. Khare, K. Rajasekhar, S. Ramakumar and T. Govindaraju, Org. Biomol. Chem., 2018, Advance Article , DOI: 10.1039/C8OB01691G

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