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From a multitarget antidiabetic glycosyl isoflavone towards new molecular entities against diabetes and Alzheimer’s disease : generation of lead series and target assessment
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Advisor(s)
Abstract(s)
Type 2 diabetes and Alzheimer’s disease are closely related amyloid diseases globally affecting millions of people. However, the pathophysiological mechanisms connecting both diseases still require further investigation. In this work, we compile the existing evidence in the literature to allow the establishment of etiological links needed for drug discovery against diabetes-induced dementia. Furthermore, we provide an extensive revision of bioactive lead molecules that encourage further studies, particularly focusing on polyphenol sugar conjugates endowed with antidiabetic and neuroprotective activities.
The state-of-the-art synthetic approaches for the generation of these types of molecules are also covered, thus setting the organic chemistry background for the original research work here developed.
The use of carbohydrate-based molecules in drug research and development has multiple recognized benefits. In addition to enhanced solubility, bioavailability, and antidiabetic effects as previously reported, in this work we show, for the first time, that C-glucosylation is able to reverse the membrane dipole potential decrease induced by planar lipophilic polyphenols, elsewhere described as Pan-Assay Interference Compounds. This is a relevant discovery for drug development, particularly in the context of this thesis due to the polyphenolic nature of the compounds here presented.
One of these compounds, 8-β-D-glucosylgenistein, was investigated in a diet-induced obese mouse of type 2 diabetes and found to exert a multitarget antidiabetic mechanism of action that goes beyond prior conjectures. Indeed, this antihyperglycemic glucosyl isoflavone reduces the renal threshold for glucose reabsorption, ameliorates diabetes-associated non-alcoholic fatty liver disease and hypercholesterolemia, normalizes insulin-degrading enzyme expression, and increases glucosestimulated insulin secretion. However, the detected inability of this polyphenol to permeate the blood brain barrier and to exert neuroprotective effects encouraged the pursuit of new scaffolds with therapeutic potential against diabetes-induced dementia.
The role of amyloid β in the neurodegenerative processes occurring in Alzheimer’s disease and diabetes-induced dementia is, nowadays, unquestionable. Yet, targeted therapies aimed at inhibiting amyloid secretion or aggregation have, so far, failed clinical trials. In the past decade, the role of the cellular prion protein (PrPC) – a high-affinity ligand of amyloid β oligomers (Aβo) – has, in fact, been regarded as the limiting step in the cascade of events leading to neurodegeneration. Fyn kinase is one of the key players in this cascade, which culminates with the formation of neurofibrillary tangles composed by hyperphosphorylated tau, eventually leading to cell death. In this perspective, we have identified innovative N-methylpiperazinyl flavones and their glucosyl derivatives as Aβo-binders and non-toxic disruptors of Aβo-PrPC interactions. Furthermore, easily accessed glucosyl polyphenols with improved pharmacokinetic properties were also investigated and revealed to inhibit Aβ-induced Fyn activation with concomitant decrease in tau phosphorylation. Fyn kinase inhibition is considered a novel therapeutic strategy for Alzheimer’s disease, and these compounds are the first to accomplish this goal, with proven downstream effects. These molecules thus share the potential for further development against Alzheimer’s disease and diabetes-induced dementia.
The work presented in this thesis elucidates the therapeutic relevance of natural and nature-inspired C-glucosyl polyphenols in the studied biological context, and highlights the usefulness of carbohydrate-based molecules for medicinal chemistry applications.
Description
Keywords
Type 2 Diabetes Alzheimer’s Disease Diabetes-Induced Dementia C-Glucosyl Polyphenols Pan-Assay Interference Compounds Amyloid β Oligomers Cellular Prion Protein Fyn Kinase Hyperphosphorylated Tau