Designing multi-target-directed flavonoids: a strategic approach to Alzheimer's disease.

The underlying causes of Alzheimer's disease (AD) remain a mystery, with multiple pathological components, including oxidative stress, acetylcholinesterase, amyloid-ß, and metal ions, all playing a role. Here we report a strategic approach to designing flavonoids that can effectively tackle multiple pathological elements involved in AD. Our systematic investigations revealed key structural features for flavonoids to simultaneously target and regulate pathogenic targets. Our findings led to the development of a highly promising flavonoid that exhibits a range of functions, based on a complete structure-activity relationship analysis. Furthermore, our mechanistic studies confirmed that this flavonoid's versatile reactivities are driven by its redox potential and direct interactions with pathogenic factors. This work highlights the potential of multi-target-directed flavonoids as a novel solution in the fight against AD.

Novel conformation of hyaluronic acid with improved cosmetic efficacy.

BACKGROUND: Hyaluronic acid presents a valuable cosmetic ingredient that occurs naturally. Its direct links to skin aging has led to its broad application. The aim of this study was to improve the cosmetic efficacy of high molecular weight hyaluronic acid (HMWHA) without chemical modifications and evaluate such improvements through clinical and in vitro studies. METHODS: A novel formulation of HMWHA (SCAI-HA) was prepared and investigated to comparatively assess 6 clinical and 2 in vitro parameters concerning its dermatological cosmetic efficacy and biological properties. The dermatological and cellular parameters examined in this study include skin hydration, transepidermal water loss (TEWL), skin elasticity, wrinkles, facial sagging, dermal density, cytotoxicity, and collagen synthesis. RESULTS: SCAI-HA exhibited the ability to improve the tested dermatological parameters (hydration, elasticity, wrinkles, and density) to magnitudes comparable to those of HMWHA. In addition, SCAI-HA showed notably improved capacities for attenuating facial sagging and TEWL and promoting cellular collagen synthesis in normal human dermal fibroblasts. CONCLUSION: SCAI-HA presents a novel conformation of HMWHA with improved cosmetic efficacy in mitigating (i) facial sagging, (ii) TEWL, and promoting, and (iii) collagen synthesis. These findings denote the enhancement of SCAI-HA as a cosmetic ingredient with potential anti-aging properties.

Drug repurposing: small molecules against Cu(II)-amyloid-ß and free radicals.

Alzheimer's disease (AD) presents a complex pathology entangling numerous pathological factors, including amyloid-ß (Aß), metal ions, and reactive oxygen species (ROS). Increasing evidence reveals pathological connections among these distinct components in AD. For instance, the association between the amyloid cascade and metal ion hypotheses has introduced a novel pathogenic target: metal-bound Aß. Investigation of such interconnections requires substantial research and can be expedited by chemical reagents that are able to modify multiple pathogenic factors in AD. Drug repurposing is an efficient approach for rediscovering previously utilized molecules with desirable biological and pharmaceutical properties as chemical reagents. Herein, we report the evaluation of three pre-approved drug molecules, selected based on their chemical structure and properties, as chemical reagents that can be used for elucidating the complicated pathology of AD.

A Glycosylated Prodrug to Attenuate Neuroinflammation and Improve Cognitive Deficits in Alzheimer's Disease Transgenic Mice.

We report a prodrug, Glu-DAPPD, to overcome the shortcomings of an anti-neuroinflammatory molecule, N,N'-diacetyl-p-phenylenediamine (DAPPD), in biological applicability for potential therapeutic applications. We suspect that Glu-DAPPD can release DAPPD through endogenous enzymatic bioconversion. Consequently, Glu-DAPPD exhibits in vivo efficacies in alleviating neuroinflammation, reducing amyloid-ß aggregate accumulation, and improving cognitive function in Alzheimer's disease transgenic mice. Our studies demonstrate that the prodrug approach is suitable and effective toward developing drug candidates against neurodegeneration.

Minimalistic Principles for Designing Small Molecules with Multiple Reactivities against Pathological Factors in Dementia.

Multiple pathogenic elements, including reactive oxygen species, amyloidogenic proteins, and metal ions, are associated with the development of neurodegenerative disorders. We report minimalistic redox-based principles for preparing compact aromatic compounds by derivatizing the phenylene moiety with various functional groups. These molecular agents display enhanced reactivities against multiple targets such as free radicals, metal-free amyloid-ß (Aß), and metal-bound Aß that are implicated in the most common form of dementia, Alzheimer's disease (AD). Mechanistic studies reveal that the redox properties of these reagents are essential for their function. Specifically, they engage in oxidative reactions with metal-free and metal-bound Aß, leading to chemical modifications of the Aß peptides to form covalent adducts that alter the aggregation of Aß. Moreover, the administration of the most promising candidate significantly attenuates the amyloid pathology in the brains of AD transgenic mice and improves their cognitive defects. Our studies demonstrate an efficient and effective redox-based strategy for incorporating multiple functions into simple molecular reagents.

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

Neurotoxic implications of the interactions between Cu(I/II) and amyloid-ß (Aß) 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 Aß utilizing a rationally designed peptide modifier, L1. Upon reacting with L1, a metal-binding histidine (His) residue, His14, in Cu(II)-Aß was modified through either covalent adduct formation, oxidation, or both. Consequently, the reactivity of L1 with Cu(II)-Aß was able to disrupt binding of Cu(II) to Aß and result in chemically modified Aß with altered aggregation and toxicity profiles. Our molecular-level mechanistic studies revealed that such L1-mediated modifications toward Cu(II)-Aß could stem from the molecule's ability to 1) interact with Cu(II)-Aß and 2) foster copper-O2 chemistry. Collectively, our work demonstrates the development of an effective approach to modify Cu(II)-Aß at a metal-binding amino acid residue and consequently alter Aß's coordination to copper, aggregation, and toxicity, supplemented with an in-depth mechanistic perspective regarding such reactivity.

Multiple reactivities of flavonoids towards pathological elements in Alzheimer's disease: structure-activity relationship.

Amyloid-ß (Aß) accumulation, metal ion dyshomeostasis, oxidative stress, and cholinergic deficit are four major characteristics of Alzheimer's disease (AD). Herein, we report the reactivities of 12 flavonoids against four pathogenic elements of AD: metal-free and metal-bound Aß, free radicals, and acetylcholinesterase. A series of 12 flavonoids was selected based on the molecular structures that are responsible for multiple reactivities including hydroxyl substitution and transfer of the B ring from C2 to C3. Our experimental and computational studies reveal that the catechol moiety, the hydroxyl groups at C3 and C7, and the position of the B ring are important for instilling multiple functions in flavonoids. We establish a structure-activity relationship of flavonoids that should be useful for designing chemical reagents with multiple reactivities against the pathological factors of AD.

Impact of sphingosine and acetylsphingosines on the aggregation and toxicity of metal-free and metal-treated amyloid-ß.

Pathophysiological shifts in the cerebral levels of sphingolipids in Alzheimer's disease (AD) patients suggest a link between sphingolipid metabolism and the disease pathology. Sphingosine (SP), a structural backbone of sphingolipids, is an amphiphilic molecule that is able to undergo aggregation into micelles and micellar aggregates. Considering its structural properties and cellular localization, we hypothesized that SP potentially interacts with amyloid-ß (Aß) and metal ions that are found as pathological components in AD-affected brains, with manifesting its reactivity towards metal-free Aß and metal-bound Aß (metal-Aß). Herein, we report, for the first time, that SP is capable of interacting with both Aß and metal ions and consequently affects the aggregation of metal-free Aß and metal-Aß. Moreover, incubation of SP with Aß in the absence and presence of metal ions results in the aggravation of toxicity induced by metal-free Aß and metal-Aß in living cells. As the simplest acyl derivatives of SP, N-acetylsphingosine and 3-O-acetylsphingosine also influence metal-free Aß and metal-Aß aggregation to different degrees, compared to SP. Such slight structural modifications of SP neutralize its ability to exacerbate the cytotoxicity triggered by metal-free Aß and metal-Aß. Notably, the reactivity of SP and the acetylsphingosines towards metal-free Aß and metal-Aß is determined to be dependent on their formation of micelles and micellar aggregates. Our overall studies demonstrate that SP and its derivatives could directly interact with pathological factors in AD and modify their pathogenic properties at concentrations below and above critical aggregation concentrations.

N,N'-Diacetyl-p-phenylenediamine restores microglial phagocytosis and improves cognitive defects in Alzheimer's disease transgenic mice.

As a central feature of neuroinflammation, microglial dysfunction has been increasingly considered a causative factor of neurodegeneration implicating an intertwined pathology with amyloidogenic proteins. Herein, we report the smallest synthetic molecule (N,N'-diacetyl-p-phenylenediamine [DAPPD]), simply composed of a benzene ring with 2 acetamide groups at the para position, known to date as a chemical reagent that is able to promote the phagocytic aptitude of microglia and subsequently ameliorate cognitive defects. Based on our mechanistic investigations in vitro and in vivo, 1) the capability of DAPPD to restore microglial phagocytosis is responsible for diminishing the accumulation of amyloid-ß (Aß) species and significantly improving cognitive function in the brains of 2 types of Alzheimer's disease (AD) transgenic mice, and 2) the rectification of microglial function by DAPPD is a result of its ability to suppress the expression of NLRP3 inflammasome-associated proteins through its impact on the NF-κB pathway. Overall, our in vitro and in vivo investigations on efficacies and molecular-level mechanisms demonstrate the ability of DAPPD to regulate microglial function, suppress neuroinflammation, foster cerebral Aß clearance, and attenuate cognitive deficits in AD transgenic mouse models. Discovery of such antineuroinflammatory compounds signifies the potential in discovering effective therapeutic molecules against AD-associated neurodegeneration.

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-ß (Aß) 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 Aß 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 Aß isoforms, Aß40 and Aß42, as well as the production of toxic Aß 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.

Orobol: An Isoflavone Exhibiting Regulatory Multifunctionality against Four Pathological Features of Alzheimer's Disease.

We report orobol as a multifunctional isoflavone with the ability to (i) modulate the aggregation pathways of both metal-free and metal-bound amyloid-ß, (ii) interact with metal ions, (iii) scavenge free radicals, and (iv) inhibit the activity of acetylcholinesterase. Such a framework with multifunctionality could be useful for developing chemical reagents to advance our understanding of multifaceted pathologies of neurodegenerative disorders, including Alzheimer's disease.

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.

Strategic Design of 2,2'-Bipyridine Derivatives to Modulate Metal-Amyloid-ß Aggregation.

The complexity of Alzheimer's disease (AD) stems from the inter-relation of multiple pathological factors upon initiation and progression of the disease. To identify the involvement of metal-bound amyloid-ß (metal-Aß) aggregation in AD pathology, among the pathogenic features found in the AD-affected brain, small molecules as chemical tools capable of controlling metal-Aß aggregation were developed. Herein, we report a new class of 2,2'-bipyridine (bpy) derivatives (1-4) rationally designed to be chemical modulators toward metal-Aß aggregation over metal-free Aß analogue. The bpy derivatives were constructed through a rational design strategy employing straightforward structural variations onto the backbone of a metal chelator, bpy: (i) incorporation of an Aß interacting moiety; (ii) introduction of a methyl group at different positions. The newly prepared bpy derivatives were observed to bind to metal ions [i.e., Cu(II) and Zn(II)] and interact with metal-Aß over metal-free Aß to varying degrees. Distinguishable from bpy, the bpy derivatives (1-3) were indicated to noticeably modulate the aggregation pathways of Cu(II)-Aß and Zn(II)-Aß over metal-free Aß. Overall, our studies of the bpy derivatives demonstrate that the alteration of metal binding properties as well as the installation of an Aß interacting capability onto a metal chelating framework, devised via the rational structure-based design, were able to achieve evident modulating reactivity against metal-Aß aggregation. Obviating the need for complicated structures, our design approach, presented in this work, could be appropriately utilized for inventing small molecules as chemical tools for studying desired metal-related targets in biological systems.

Cell death mechanistic study of photodynamic therapy against breast cancer cells utilizing liposomal delivery of 5,10,15,20-tetrakis(benzo[b]thiophene) porphyrin.

5,10,15,20-Tetrakis(benzo[b]thiophene) porphyrin (BTP) is a newly synthesized hydrophobic photosensitizer with fluorescence quantum yield in toluene: ΦF=0.062. Previously, its limitations in solubility had hindered scientific experimentation regarding its photodynamic effects on cancer cells. By utilizing various compositions of liposomes in order to alter the solubility of BTP, the photocytotoxicity, reactive oxygen species generation, and subcellular localization of the liposomal BTP were identified in this work. DNA fragmentation and high content screening assays were performed in order to shed light on the tumoricidal mechanism of the liposomal photosensitizer. The MTT assay results showed promising results in the irradiation specific PDT activity against MCF-7 cells in all liposomal compositions. Production of ROS was confirmed in the liposomal BTP treated MCF-7 cells after irradiation in a concentration dependent manner. The subcellular localization assays revealed that the localization of BTP was dependent on both the photosensitizer's chemical properties and the properties of the delivery agent encapsulating aforesaid substance. Significant DNA fragmentation was observed in both nucleus localizing liposomal BTP, BTP encapsulated DOPC and DOPE (DOPC-BTP and DOPE-BTP), treated MCF-7 cells. All liposomal-BTPs were successful in inducing mitochondrial permeability transition, an increase in the permeability of the mitochondrial membrane, and activating caspase-3/7. ER localizing BTP were able to significantly increase the cytosolic calcium levels by photodynamic therapy, confirming the photodynamic ability of ER localized BTP to damage the ER membrane. The application of liposomes in delivering a novel hydrophobic photosensitizer, BTP, and photodynamic therapy treatment against MCF-7 cells were successful. It was confirmed that the MCF-7 cell death pathway via photodynamic therapy was altered in a controlled manner by controlling the intracellular localization of the photosensitizer through lipid composition adjustment.

Electrocatalytic H2 Evolution by Supramolecular Ru(II)-Rh(III)-Ru(II) Complexes: Importance of Ligands as Electron Reservoirs and Speciation upon Reduction.

The supramolecular water reduction photocatalysts [{(Ph2phen)2Ru(dpp)}2RhX2](PF6)5 (Ph2phen = 4,7-diphenyl-1,10-phenanthroline, dpp =2,3-bis(2-pyridyl)pyrazine X = Cl, Br) are efficient electrocatalysts for the reduction of CF3SO3H, CF3CO2H, and CH3CO2H to H2 in DMF or DMF/H2O mixtures. The onset of catalytic current occurs at -0.82 V versus Ag/AgCl for CF3SO3H, -0.90 V for CF3CO2H, and -1.1 V for CH3CO2H with overpotentials of 0.61, 0.45, and 0.10 V, respectively. In each case, catalysis is triggered by the first dpp ligand reduction implicating the dpp as an electron reservoir in catalysis. A new species with Epc ∼ -0.75 V was observed in the presence of stoichiometric amounts of strong acid, and its identity is proposed as the Rh(H)(III/II) redox couple. H2 was produced in 72-85% Faradaic yields and 95-116 turnovers after 2 h and 435 turnovers after 10 h of bulk electrolysis. The identities of Rh(I) species upon reduction have been studied. In contrast to the expected dissociation of halides in the Rh(I) state, the halide loss depends on solvent and water content. In dry CH3CN, in which Cl(-) is poorly solvated, a [Ru] complex dissociates and [(Ph2phen)2Ru(dpp)Rh(I)Cl2](+) and [(Ph2phen)2Ru(dpp)](2+) are formed. In contrast, for X = Br(-), the major product of reduction is the intact trimetallic Rh(I) complex [{(Ph2phen)2Ru(dpp)}2Rh(I)](5+). Chloride loss in CH3CN is facilitated by addition of 3 M H2O. In DMF, the reduced species is [{(Ph2phen)2Ru(dpp)}2Rh(I)](5+) regardless of X = Cl(-) or Br(-).