Molecules Webinar | Synthesis and Identification of Small Compounds Active in Neurodegeneration
Welcome from the Chair
11th Molecules Webinar
Synthesis and Identification of Small Compounds Active in Neurodegeneration
Neurodegenerative diseases of the nervous system impose substantial medical and public health burdens on populations throughout the world. Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis are three of the major neurodegenerative diseases with increasing incidence worldwide, associated with the ageing of the population. Several pathological hallmarks have been widely recognized as causes of the loss of specific neurons , including the misfolding and deposition of proteins, oxidative stress and neuroinflammation. Despite increasing awareness and significant research advancements, leading to treatment options that provide a significantly increased quality of life and life expectancy, a delay in the progression of disease and a reduction in symptoms, the development of efficacious therapies has not yet been achieved in this field.
Better elucidation of the molecular mechanisms involved in neurodegenerative diseases can provide an important theoretical basis for the discovery of new and effective strategies for symptomatic treatment. Currently, the development of drugs for the treatment of neurological diseases is limited by the complex challenges posed by the blood–brain barrier, which make it difficult to transport drugs to the brain tissue. Nanosized drug delivery systems are specifically engineered to shuttle drugs across the blood–brain barrier. Moreover, the development of multi-target therapeutics has become an important approach that is widely used in the research in this area, envisaging simultaneous interaction with several pathological targets.
This webinar aims to explore new mechanisms that can serve as targets of therapeutic interventions, as well as some pharmaceutical and pharmacological aspects of neurodegenerative management.
Date: 17 June 2021
Time: 5:00pm CEST | 11:00am EDT | 11:00pm CST Asia
Webinar ID: 891 6385 2550
Webinar Secretariat: molecules.webinar@mdpi.com
Chair
The stilbene skeleton is found in at least 70 plant species, a number of which are dietary components, including grapes, mulberries, and peanuts. The stilbene scaffold has attracted much interest in the past decade because it is a well-known natural antioxidant. There are several comprehensive reviews and scientific reports available focusing on the multiple pharmacological activities of stilbene-containing compounds, such as anti-inflammatory and neuroprotective effects, thanks to their inhibition of the production of different reactive oxygen species, as well as the activation of PPARs, transcriptional factors controlling the expression of several genes involved in energetic balance and in neuroprotection in neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. This talk is an overview of my research results with regard to stilbene derivatives, which are phenols or hybrid compounds with different mechanisms of action. This talk focuses on their neurodegeneration, pharmacokinetics and SAR studies.
Dr. Barbara De Filippis has a degree in Pharmaceutical Chemistry and Technology and earned her PhD in Medicinal Chemistry Sciences at the University of Chieti (Italy), where she is currently an Assistant Professor of Medicinal Chemistry. Her main expertise deals with the design and synthesis of stilbene derivatives with multiple pharmacological potential. Over the past several years, the principal interest of Dr. De Filippis’ research group was related to the studies of PPARs involved in metabolic diseases [e.g., B. De Filippis et al., Structural development studies of PPARs ligands based on tyrosine scaffold, European Journal of Medicinal Chemistry, 89, 817-825, 2015; B. De Filippis et al., In vitro protective effects of resveratrol and stilbene alkanoic derivatives on induced oxidative stress on C2C12 and MCF7 cells. J Biol Regul Homeost Agents 31(3), 589-601, 2017] and the synthesis of fibrate derivatives with different isoform selectivity. Her current research interests have shifted toward the design and the synthesis of natural polyphenol derivatives, in particular resveratrol and caffeic acid, with their anticancer, antioxidant and antimicrobial biological activities, among others [e.g., B. De Filippis et al., Synthesis and cytotoxic effects on pancreatic cancer cells of resveratrol analogs. Medicinal Chemistry Research 28, 984-991, 2019; B. De Filippis et al., Synthesis and Biological Evaluation of Halogenated E-Stilbenols as Promising Antiaging Agents. Molecules 2020, 25, 5770; B. De Filippis et al., Searching for new tools to counteract the Helicobacter pylori resistance: the positive action of resveratrol derivatives. Antibiotics, 2020 9, 891]. She has co-authored more than 60 scientific articles.
Invited Speakers
University of California San Diego (UCSD), United States
In Alzheimer’s disease and related neurodegenerative tauopathies, the aggregation of the microtubule (MT)-associated protein tau is believed to have neuropathological consequences that result from toxic gains and/or losses of tau functions. Brain-penetrant MT-stabilizing compounds, including selected natural products such as epothilone D and dictyostatin, as well as selected non-naturally occurring compounds belonging to the triazolopyrimidine class, have been found to be effective in animal models of neurodegenerative tauopathies due to their ability to compensate for MT deficits in the CNS. This presentation will provide an overview of the findings from preclinical studies and ongoing efforts in the development of triazolopyrimidines as potential candidates.
Dr. Ballatore is a Professor at the University of California San Diego (UCSD) Skaggs School of Pharmacy and Pharmaceutical Sciences and a medicinal chemist with ~20 years of experience in drug discovery in both the biotechnology (~3 years) and academic drug discovery settings. Over the past several years, the primary focus of Dr. Ballatore’s research has been in the area of Alzheimer’s disease and related neurodegenerative tauopathies with specific collaborative programs directed towards the discovery and development of (a) tau aggregation inhibitors [e.g., Bioorg. Med. Chem., 2012, 20, 4451–61]; (b) microtubule-stabilizing agents [e.g., see J. Med. Chem., 2014, 57(14): 6116-27; J. Med. Chem., 2021, 64: 1073-102]; (c) thromboxane A2 receptor antagonists [e.g., see ACS Chem. Neurosci., 2012, 3(11): 928-40]; and (d) multi-targeted inhibitors of eicosanoid biosynthesis [e.g., see J. Med. Chem., 2017, 60(12), 5120-45]. In addition, the Ballatore laboratory is also actively involved in the investigation of the basic, fundamental principles of medicinal chemistry, such as in the area of isosteric replacements [e.g., see J. Med. Chem., 2016, 59(7), 3183-203; Eur. J. Med. Chem., 2021, 218, 113399].
Protein aggregation is the hallmark of all neurodegenerative diseases. A high-throughput screen was set up to monitor protein aggregation resulting from the expression of mutant superoxide dismutase I. Three chemotypes were identified, each of which was optimized to arrive at three orally active, CNS-penetrable inhibitors of protein aggregation with good pharmacokinetic profiles, exhibiting low toxicity in mice without off-target effects. One of the three compounds (referred to as NU-9) was applied to determine its effect on upper motor neurons in two mouse models with different mutations that led to protein aggregation. The upper motor neurons in these mice were fluorescently labeled so that effects specific to these neurons could be monitored. NU-9 stabilized the upper motor neurons, reduced protein aggregation, improved the health of apical dendrites, maintained or enhanced the axon length, and improved the health of mitochondria and the endoplasmic reticulum without an effect on body weight. In an inverted mesh test, treated mice performed equivalent to wild-type mice, whereas untreated mice experienced a decline much sooner.
Dr. Richard B. Silverman is the Patrick G. Ryan/Aon Professor in the Departments of Chemistry, Molecular Biosciences, and Pharmacology, Northwestern University, U.S.A. His research involves the design, synthesis, and evaluation of enzyme inhibitors and protein aggregation inhibitors for the treatment of CNS diseases and disorders, as well as cancer. He has authored or co-authored 385 research articles and reviews, 120 United States and foreign patents, and five books. He has been elected to the American Academy of Arts and Sciences and the National Academy of Inventors, was inducted into the American Chemical Society Medicinal Chemistry Hall of Fame, and has received many national and international awards for his research.
University of Porto, Portugal,
University of Santiago de Compostela, Spain
Selective central nervous system drug development and delivery are among the major challenges in medicinal chemistry. There is a high number of patients suffering from neurodegenerative disorders worldwide and very low efficacy in the reduced arsenal of available treatments. Understanding some of the molecular changes associated with these ubiquitous and widespread diseases has stimulated efforts to develop drugs that specially interact with key targets. The computer-assisted design and synthesis of potent small molecules [1-3] and the development of new carriers [4] allow a wide range of possibilities for targeted therapies. Knowledge of biochemical processes creates the opportunity to provide treatments that are potentially less toxic and more effective than traditional therapeutic strategies. This presentation will describe the different approaches and illustrate their successful implementation in the search for better treatments for neurodegenerative diseases.
Dr. Matos is a Researcher in Medicinal Chemistry at the Department of Chemistry and Biochemistry, University of Porto, and a Visitor at the Faculty of Pharmacy, University of Santiago de Compostela. Her research interests include new tools for drug discovery and delivery, particularly in the field of neurodegenerative diseases. To date, Dr. Matos has authored 108 articles in peer-reviewed journals, as well as 5 book chapters, 1 patent and 43 refereed conference publications (h-index 30). Dr Matos established her scientific career via fruitful collaborations with both academic and industrial partners. Finally, Dr. Matos is a member of the International Editorial Board of ChemMedChem and the Medicinal Chemistry Section of Molecules and has served as a Guest Editor for Current Topics in Medicinal Chemistry, Molecules and ACS Medicinal Chemistry Letters.
The pathogenesis of Alzheimer’s disease (AD) with late onset (LOAD) is understood to occur as a result of multiple factors. The neuropathological features include extracellular senile plaques, containing beta-amyloid peptides (Aβ), and intracellular neurofibrillary tangles composed of paired helical tau proteins. Both proteins have been associated with neuronal loss and atrophy of the cerebral cortex. Thus, misfolded proteins seem to contribute to pathogenesis, but are not the only contributors. The currently approved drugs only attenuate symptoms, without curing the disease. Research into AD has experienced several failures in terms of the development of disease-modifying therapies and thus, in order to develop a causal therapy, new targets are desperately required. Mitochondria are among these targets since mitochondrial dysfunction occurs early in the disease process and may represent the missing link between ageing and LOAD. Mitochondria are an important target for natural compounds and pharmaceuticals, including polyphenols and pirinixic acid derivates. In particular, chemically modified natural compounds may represent a new class of agents against LOAD.
Dr. Gunter P. Eckert studied food chemistry and environmental toxicology and holds a Ph.D. in pharmacology. He is a trained pharmacologist and a Full Professor for Nutrition in Prevention and Therapy at the Institute for Nutritional Sciences at the Justus-Liebig-University Giessen, Germany. He has worked in the area of nutrition-based prevention and therapy of age-related neurodegenerative diseases for many years, at the interface of nutrition and pharma, with a strong focus on mitochondrial function [e.g., Pohland M et al. MH84 improves mitochondrial dysfunction in a mouse model of early Alzheimer's Alzheimers Res Ther, 2018; 10(1):18.; Grewal R, et al. Purified Oleocanthal and Ligstroside protect against mitochondrial dysfunction in models of early Alzheimer’s Disease and brain ageing. Exp Neurol. 2020, 328:113248]. He has intensive experience in managing research projects and has published more than 135 scientific articles.
Webinar Content
Program
|
Speaker/Presentation |
Time in CEST |
|
Dr. Barbara De Filippis Chair Introduction |
5:00 - 5:05 pm |
|
Dr. Barbara De Filippis Stilbene, a Useful Scaffold in the Design of Neuroprotective Agents |
5:05 - 5:25 pm |
|
Prof. Dr. Carlo Ballatore Microtubule Stabilizing Triazolopyrimidines as Potential Candidates for the Treatment of Alzheimer’s Disease and Related Tauopathies |
5:25 - 5:45 pm |
|
Prof. Dr. Richard B. Silverman Protein Aggregation and the Development of Therapeutics for Upper Motor Neuron Diseases |
5:45 - 6:05 pm |
|
Prof. Dr. Maria João Matos Coumarin-Inspired Hybrids as Promising Agents against Neurodegenerative Diseases |
6:05 - 6:25 pm |
|
Prof. Dr. Gunter P. Eckert Mitochondrial Dysfunction as a Target for New Compounds against Alzheimer’s Disease |
6:25 - 6:45 pm |
|
Q&A Session |
6:45 - 7:10 pm |
|
Closing of Webinar |
7:10 - 7:15 pm |
Relevant SI
Synthesis and Identification of Small Compounds Active in Neurodegeneration in Molecules
Synthesis and Identification of Small Compounds Active in Neurodegeneration in Chemistry
Guest Editor: Dr. Barbara De Filippis
Co-Guest Editor: Prof. Dr. Gunter P. Eckert
Deadline for manuscript submissions: 30 September 2021
Sponsors and Partners
Organizers
