Identification of small molecules with reactivities against multiple pathogenic elements of alzheimer???s disease

Department of ChemistryAlzheimer???s disease (AD) remains a formidable threat against mankind since its introduction in 1906. As a progressive neurodegenerative disease responsible for the majority of dementia cases, AD remains cureless. Along with the lack of an effective cure, the aging world population depicts an imminent epidemic and pessimistic outlook regarding the disease. Research endeavors dedicated to understanding the etiopathology of AD and developing therapeutics have led to significant progress in our comprehension of AD. However, attempts of formulating treatments with the ability to stop AD progression have proven futile. More specifically, various pathological factors have been identified and implicated as sources of neurodegeneration leading to AD. These include amyloid-??? (A???), metal ions, acetylcholinesterase (AChE), and reactive oxygen species (ROS) indicated in the various hypotheses attempting to elucidate the main cause of AD: amyloid cascade, metal ion, cholinergic, and oxidative stress, respectively. Therapeutic approaches targeting these individual pathogenic features have yet to result in clinically effective treatment strategies. Such failures have led to a shift in paradigm to understand the interconnections between these pathological factors to account for AD???s complexity. Intricacies of the pathogenic elements of AD present experimental challenges in investigating their inter-relationships. Multifunctional molecules capable of targeting multiple pathogenic factors of AD could, therefore, be beneficial in our attempt to understand AD. In this thesis, we first aim to identify molecular frameworks conferring multifunctionality against multiple pathogenic factors of AD [i.e., A???, metal-bound A??? (metal???A???), AChE, and ROS] from the structures of both natural products and synthetic molecules. Such chemical entities will be helpful in furthering our understanding of the relationships among the different pathological factors and assist the development of physiologically viable chemical tools with suitable bioapplicability. We hope that these findings contribute towards an improved capacity for experimentally examining the complex network of AD pathology and a closer understanding of its inner workings. In Chapter 1, we briefly introduce the multifaceted pathology of AD and discuss the various pathogenic elements implicated in driving the development and progression of the disease. In Chapter 2, a naturally occurring isoflavone, orobol, is presented as a multifunctional molecule with modulative reactivity against four specific pathogical factors of AD: metal-free A???, metal???A???, ROS, and AChE. In chapter 3, the molecular structures of 12 flavonoids, selected based on three multifunctional flavonoids (i.e., quercetin, luteolin, and orobol) were examined with respect to their reactivities against metalfree A???, metal???A???, ROS, and AChE. This study aimed to identify the molecular features responsible for instilling these flavonoids with the ability to modulate the aforementioned targets. Four major structural attributes were identified to contribute to such versatility of select flavonoids. In chapter 4, pre-approved anti-depressant molecules were explored as candidates of drug repurposing to discover new multifunctional molecules against AD and increase our database of structural moieties associated with multifunctionality. The versatile reactivity of three synthetic compounds were demonstrated against Cu(II)???A???, free radicals, and AChE. Overall, we present a number of multifunctional chemicals capable of targeting several major pathogenic elements of AD. We believe that these molecules will contribute significantly towards our efforts to better comprehend the multifaceted etiopathology of AD by serving as chemical tools that allow us to directly perform experiments regarding the pathogenic connections between metal-free A???, metal???A???, ROS, and AChE at in vitro and possibly clinical stages. Moreover, identification of the structural features instilling multifunctionality could facilitate the design and development of biocompatible therapeutics capable of simultaneously targeting multiple pathologies of AD and their connections. Our approaches will provide the foundation for developing effective and efficient methods of elucidating fundamental connections among the pathological factors of AD at the molecular level and identifying efficacious therapeutics against AD capable of controlling the progression of neurodegeneration.clos

Chemical Insights into Topical Agents in Intraocular Pressure Management: From Glaucoma Etiopathology to Therapeutic Approaches

Glaucoma encompasses a group of optic neuropathies characterized by complex and often elusive etiopathology, involvihttng neurodegeneration of the optic nerve in conjunction with abnormal intraocular pressure (IOP). Currently, there is no cure for glaucoma, and treatment strategies primarily aim to halt disease progression by managing IOP. This review delves into the etiopathology, diagnostic methods, and treatment approaches for glaucoma, with a special focus on IOP management. We discuss a range of active pharmaceutical ingredients used in glaucoma therapy, emphasizing their chemical structure, pharmacological action, therapeutic effectiveness, and safety/tolerability profiles. Notably, most of these therapeutic agents are administered as topical formulations, a critical aspect considering patient compliance and drug delivery efficiency. The classes of glaucoma therapeutics covered in this review include prostaglandin analogs, beta blockers, alpha agonists, carbonic anhydrase inhibitors, Rho kinase inhibitors, and miotic (cholinergic) agents. This comprehensive overview highlights the importance of topical administration in glaucoma treatment, offering insights into the current state and future directions of pharmacological management in glaucoma

Intertwined Pathologies of Amyloid-beta and Metal Ions in Alzheimer's Disease: Metal-Amyloid-beta

Both amyloid-beta (A beta) and metal ions are implicated in the pathology of Alzheimer's disease (AD). Research efforts elucidating the pathogenic roles of these two biological components denote a connection between them. This highlight review presents the current understanding of A beta and metal ions in AD and their relationship prompting a hybrid concept: metal-bound A beta (metal-A beta)

The Application of Bactericidal Silver Nanoparticles in Wound Treatment

Even with the prevalence of wounds, the medical technol‐ ogy for efficiently managing skin damage is still primitive. The disruption of any of the numerous healing processes can lead to problems in the time-sensitive healing actions of the dermal and epidermal layers. Bacterial infection is one of the major obstacles to proper wound healing as it poses a danger of causing long-term negative effects. Keeping the wound free of bacteria is imperative to the proper and hasty repair of dermal wounds. Silver has been widely used to treat wounds for its bactericidal properties. Although the mechanism of silver’s antibacterial action is not fully understood, it exhibits a significant antimicrobial efficacy against a wide spectrum of bacterial species. A number of different approaches to the mechanism are reported and presented in this review. Silver nanoparticles (AgNPs) have been reported to exhibit enhanced antibac‐ terial activity due to their increased surface-area-to-volume ratio. AgNPs are capable of various modifications, signifi‐ cantly broadening the therapeutic properties of the mate‐ rial as a result. This review explores the different aspects of silver and silver nanoparticles, and their antibacterial properties, which can be applied in the field of wound treatments

Key Physicochemical and Biological Factors of the Phase Behavior of Tau

Recent findings have garnered a substantial amount of attention toward tau based on its pathological contribution to neurodegenerative diseases, such as Alzheimer's disease (AD). Studies investigating the structure and aggregation of tau under various in vitro and in vivo conditions have revealed its intrinsically disordered structures and amyloidogenesis process. The aggregation behavior of tau is strongly dependent on the experimental conditions due to the high sensitivity of both the soluble tau conformations and the amyloid nucleation process toward its surrounding environments. Herein, we review and discuss (1) the effects of different physicochemical and biological factors as well as intermolecular interactions with various molecular chaperones on tau aggregation, (2) context-dependent liquid-liquid phase separation of tau and its amyloidogenic transformation, and (3) the utility of the phase diagram in comprehending the phase transition and separation of proteins

Chemical strategies to modify amyloidogenic peptides using iridium(III) complexes: coordination and photo-induced oxidation

Amyloidogenic peptides are considered central pathological contributors towards neurodegeneration as observed in neurodegenerative disorders [e.g., amyloid-?? (A??) peptides in Alzheimer's disease (AD)]; however, their roles in the pathologies of such diseases have not been fully elucidated since they are challenging targets to be studied due to their heterogeneous nature and intrinsically disordered structure. Chemical approaches to modify amyloidogenic peptides would be valuable in advancing our molecular-level understanding of their involvement in neurodegeneration. Herein, we report effective chemical strategies for modification of A?? peptides (i.e., coordination and coordination-/photo-mediated oxidation) implemented by a single Ir(III) complex in a photo-dependent manner. Such peptide variations can be achieved by our rationally designed Ir(III) complexes (Ir-Me, Ir-H, Ir-F, and Ir-F2) leading to significantly modulating the aggregation pathways of two main A?? isoforms, A??40 and A??42, as well as the production of toxic A?? species. Overall, we demonstrate chemical tactics for modification of amyloidogenic peptides in an effective and manageable manner utilizing the coordination capacities and photophysical properties of transition metal complexes

Development of Multifunctional Molecules as Potential Therapeutic Candidates for Alzheimer???s Disease, Parkinson???s Disease, and Amyotrophic Lateral Sclerosis in the Last Decade

Neurodegenerative diseases pose a substantial socioeconomic burden on society. Unfortunately, the aging world population and lack of effective cures foreshadow a negative outlook. Although a large amount of research has been dedicated to elucidating the pathologies of neurodegenerative diseases, their principal causes remain elusive. Metal ion dyshomeostasis, proteopathy, oxidative stress, and neurotransmitter deficiencies are pathological features shared across multiple neurodegenerative disorders. In addition, these factors are proposed to be interrelated upon disease progression. Thus, the development of multifunctional compounds capable of simultaneously interacting with several pathological components has been suggested as a solution to undertake the complex pathologies of neurodegenerative diseases. In this review, we outline and discuss possible therapeutic targets in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis and molecules, previously designed or discovered as potential drug candidates for these disorders with emphasis on multifunctionality. In addition, underrepresented areas of research are discussed to indicate new directions

Mechanistic approaches for chemically modifying the coordination sphere of copper-amyloid-beta complexes

Neurotoxic implications of the interactions between Cu(I/II) and amyloid-beta (A beta) indicate a connection between amyloid cascade hypothesis and metal ion hypothesis with respect to the neurodegeneration associated with Alzheimer's disease (AD). Herein, we report a mechanistic strategy for modifying the first coordination sphere of Cu(II) bound to A beta utilizing a rationally designed peptide modifier, L1. Upon reacting with L1, a metal-binding histidine (His) residue, His14, in Cu(II)-A beta was modified through either covalent adduct formation, oxidation, or both. Consequently, the reactivity of L1 with Cu(II)-A beta was able to disrupt binding of Cu(II) to A beta and result in chemically modified A beta with altered aggregation and toxicity profiles. Our molecular-level mechanistic studies revealed that such L1-mediated modifications toward Cu(II)-A beta could stem from the molecule's ability to 1) interact with Cu(II)A beta and 2) foster copper-O-2 chemistry. Collectively, our work demonstrates the development of an effective approach to modify Cu(II)-A beta at a metal-binding amino acid residue and consequently alter A beta's coordination to copper, aggregation, and toxicity, supplemented with an in-depth mechanistic perspective regarding such reactivity

Strategies for developing flavonoids with multiple reactivities against pathological features in Alzheimer’s disease

The etiology of Alzheimer’s disease (AD) is still unknown because of its complicated nature associated with various pathological components, including free radicals, acetylcholinesterase, and metal-free and metal-bound amyloid-beta. Thus, chemical reagents with modulating reactivities against multiple pathogenic factors are necessary for advancing our understanding of the complex pathogenesis. Here we report rational strategies for developing flavonoids that can control multiple pathological elements found in the brains of AD patients. Our investigations employing a series of flavonoids illuminated structural features critical for regulatory reactivities against desired targets. Moreover, the most promising flavonoid with multiple functions was developed based on our complete structure–activity relationship. Mechanistic studies confirmed that such versatile reactivities of the flavonoid are achieved by its redox potential and direct interactions with pathogenic factors. Overall, our studies demonstrate the feasibility of devising small molecules as multifunctional chemical reagents against pathological features found in AD