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C-Glucosyl Flavone Derivatives as Non-PAIN Therapeutic Leads for Alzheimer’s Disease
1  CQE, Faculdade de Ciências, Universidade de Lisboa
Academic Editor: Alfredo Berzal-Herranz (registering DOI)

Alzheimer’s Disease (AD) and other dementias are ranked by the WHO as the World’s 7th leading cause of death. Aiming to respond to this international public health priority, the Carbohydrate Chemistry Group of CQE-IMS has been dedicated to uncovering the AD-modifying potential of carbohydrate-based molecules. In this communication, the rational design, synthesis, and biological evaluation of C-glucosyl flavone analogs with neuroprotective activity against H2O2- and Aβ-induced cell death are explored. Furthermore, based on the well-established role of the binding between PrPC and Aβ oligomers (Aβo) for Tau hyperphosphorylation in the brain, the structural optimization process leading up to the discovery of N-methylpiperazinyl flavones and their C-glucosyl derivatives as protein-protein interaction inhibitors (PPII) against PrPC-Aβo is also presented. Importantly, because many planar lipophilic polyphenols such as the ones we have developed are Pan-Assay Interference CompoundS (PAINS), we were also interested in clarifying their ability to alter cell membrane properties in a non-specific manner. Our results show, for the first time, that well-known membrane disruptors such as resveratrol and genistein cease to reduce the membrane dipole potential when linked to a glucosyl moiety through a C-C bond, suggesting that our C-glucosides should not raise concerns regarding membrane-related PAINS-type behavior. This communication ultimately highlights the promising neuroprotective and PPII activity of C-glucosyl flavones and corresponding aglycones in the context of AD, while exploring the role of the sugar moiety in favorably tuning aglycone bioactivity, cytotoxicity, and unspecific membrane-modifying effects.

Keywords: Carbohydrate Chemistry; C-glucosylation; Neurodegeneration; PPIIs; Amyloid Disorders; Drug Discovery and Development
Comments on this paper
Markus Eriksen
Really interesting communication.