Structure–Redox–Relaxivity Relationships for Redox Responsive Manganese-Based Magnetic Resonance Imaging Probes DOI Creative Commons
Eric M. Gale, Shreya Mukherjee, Liu C

et al.

Inorganic Chemistry, Journal Year: 2014, Volume and Issue: 53(19), P. 10748 - 10761

Published: Sept. 16, 2014

A library of 10 Mn-containing complexes capable switching reversibly between the Mn(II) and Mn(III) oxidation states was prepared evaluated for potential usage as MRI reporters tissue redox activity. We synthesized N-(2-hydroxybenzyl)-N,N',N'-ethylenediaminetriacetic acid (HBET) N-(2-hydroxybenzyl-N,N',N'-trans-1,2-cyclohexylenediaminetriacetic (CyHBET) ligands functionalized (-H, -OMe, -NO2) at 5-position aromatic ring. The all 5-H 5-NO2 were isolated, but with 5-OMe unstable. (1)H relaxivity isolable measured pH 7.4 37 °C, 1.4 T. Thermodynamic stability, pH-dependent complex speciation, hydration state, water exchange kinetics complexes, pseudo-first order reduction studied using a combination pH-potentiometry, UV-vis spectroscopy, (17)O NMR measurements. effects ligand structural electronic modifications on Mn(II/III) couple by cyclic voltammetry. are potent relaxation agents compared to corresponding species [Mn(II)(CyHBET)(H2O)](2-) exhibiting 7.5-fold higher (3.3 mM(-1) s(-1)) than oxidized form (0.4 s(-1)). At 7.4, exists mixture fully deprotonated (ML) monoprotonated (HML) stability decreases become more electron-releasing (pMn μM [Mn(II)(CyHBET-R')(H2O)](2-) from 7.6 6.2 R' goes -NO2 respectively). HML speciation increases nature phenolato-O donor increases. presence coligand is maintained upon conversion ML, rate ML faster up 2 orders magnitude (k(ex)(310) H[Mn(II)(CyHBET)(H2O)](-) 1.2 × 10(8) 1.0 10(10) s(-1), can be tuned over range 0.30 V (E(1/2) = 0.27-0.57 V) through 5-substituent component. However, care must taken in tuning electronics avoid Mn(III)-ligand autoredox. Taken together, these results serve establish criteria optimizing versus differentials, potential.

Language: Английский

Microenvironment Remodeling Micelles for Alzheimer's Disease Therapy by Early Modulation of Activated Microglia DOI Creative Commons
Yifei Lü, Zhongyuan Guo, Yujie Zhang

et al.

Advanced Science, Journal Year: 2018, Volume and Issue: 6(4)

Published: Dec. 12, 2018

Current strategies for Alzheimer's disease (AD) treatments focus on pathologies in the late stage of progression. Poor clinical outcomes are displayed due to irreversible damages caused by early microglia abnormality which triggers development before identical symptoms emerge. Based crosstalk between and brain microenvironment, a reactive oxygen species (ROS)-responsive polymeric micelle system (Ab-PEG-LysB/curcumin (APLB/CUR)) is reported normalize oxidative inflammatory microenvironment reeducate from an phase AD. Through β-amyloid (Aβ) transportation-mimicked pathway, micelles can accumulate into diseased regions exert synergistic effects polymer-based ROS scavenging cargo-based Aβ inhibition upon stimuli. This multitarget strategy exhibits gradual correction efficient neuroprotection, modulation, leading decreased plaque burdens consequently enhanced cognitive functions APPswe/PSEN1dE9 model mice. The results indicate that be exploited as target AD treatment their states controlled via modulation.

Language: Английский

Citations

137
Nanotheranostics: Congo Red/Rutin‐MNPs with Enhanced Magnetic Resonance Imaging and H2O2‐Responsive Therapy of Alzheimer's Disease in APPswe/PS1dE9 Transgenic Mice DOI
Bingbing Hu, Fengying Dai, Zhanming Fan

et al.

Advanced Materials, Journal Year: 2015, Volume and Issue: 27(37), P. 5499 - 5505

Published: Aug. 13, 2015

As nanotheranostics, Congo red/Rutin-MNPs combine the abilities of diagnosis and treatment Alzheimer's disease (AD). The biocompatible nanotheranostics system based on iron oxide magnetic nanoparticles, with ultrasmall size excellent properties, can specifically detect amyloid plaques by resonance imaging, realize targeted delivery AD therapeutic agents, achieve drug controlled release H2O2 response, prevent oxidative stress. a service to our authors readers, this journal provides supporting information supplied authors. Such materials are peer reviewed may be re-organized for online delivery, but not copy-edited or typeset. Technical support issues arising from (other than missing files) should addressed Please note: publisher is responsible content functionality any Any queries content) directed corresponding author article.

Language: Английский

Citations

136
Multi-Target Directed Donepezil-Like Ligands for Alzheimer's Disease DOI Creative Commons
Mercedes Unzeta, Gerard Esteban, Irene Bolea

et al.

Frontiers in Neuroscience, Journal Year: 2016, Volume and Issue: 10

Published: May 25, 2016

HIGHLIGHTS ASS234 is a MTDL compound containing moiety from Donepezil and the propargyl group PF 9601N, potent selective MAO B inhibitor. This most advanced anti-Alzheimer agent for preclinical studies identified in our laboratory.Derived both multipotent donepezil-indolyl (MTDL-1) donepezil-pyridyl hybrids (MTDL-2) were designed evaluated as inhibitors of AChE/BuChE isoforms. MTDL-2 showed more high affinity toward four enzymes than MTDL-1.MTDL-3 MTDL-4, N-benzylpiperidinium Donepezil, metal- chelating 8-hydroxyquinoline linked to N-propargyl core they pharmacologically evaluated.The presence cyano MTDL-3, enhanced binding AChE, BuChE A. It antioxidant behavior it was able strongly complex Cu(II), Zn(II) Fe(III).MTDL-4 higher BuChE.MTDL-3 exhibited good brain penetration capacity (ADMET) less toxicity Donepezil. Memory deficits scopolamine-lesioned animals restored by MTDL-3.MTDL-3 particularly emerged ligand showing remarkable potential benefits its use AD therapy. Alzheimer's disease (AD), common form adult onset dementia, an age-related neurodegenerative disorder characterized progressive memory loss, decline language skills, other cognitive impairments. Although etiology not completely known, several factors including acetylcholine, β-amyloid deposits, τ-protein phosphorylation, oxidative stress, neuroinflammation are considered play significant roles pathophysiology this disease. For long time, patients have been treated with acetylcholinesterase such donepezil (Aricept®) but limited therapeutic success. might be due multifactorial nature AD, fact that has prompted design new Multi-Target-Directed Ligands (MTDL) based on "one molecule, multiple targets" paradigm. Thus, context, different series novel multifunctional molecules antioxidant, anti-amyloid, anti-inflammatory, metal-chelating properties interact interest pathology acetylcholinesterase, butyrylcholinesterase, monoamine oxidases A assessed biologically. review describes targets, rationale in-house library, bearing N-benzylpiperidine motif present donepezil, heterocyclic ring systems (indole, pyridine, or 8-hydroxyquinoline) special emphasis ASS234, N-propargylindole derivative. The description vitro biological compounds discussion corresponding structure-activity-relationships allows us highlight issues identification efficient

Language: Английский

Citations

131
Tacrine–Trolox Hybrids: A Novel Class of Centrally Active, Nonhepatotoxic Multi-Target-Directed Ligands Exerting Anticholinesterase and Antioxidant Activities with Low In Vivo Toxicity DOI
Eugenie Nepovimová, Jan Korábečný, Rafael Doležal

et al.

Journal of Medicinal Chemistry, Journal Year: 2015, Volume and Issue: 58(22), P. 8985 - 9003

Published: Oct. 27, 2015

Coupling of two distinct pharmacophores, tacrine and trolox, endowed with different biological properties, afforded 21 hybrid compounds as novel multifunctional candidates against Alzheimer's disease. Several them showed improved inhibitory properties toward acetylcholinesterase (AChE) in relation to tacrine. These hybrids also scavenged free radicals. Molecular modeling studies tandem kinetic analysis exhibited that these target both catalytic active site well peripheral anionic AChE. In addition, incorporation the moiety bearing antioxidant abilities displayed negligible toxicity on human hepatic cells. This striking effect was explained by formation nontoxic metabolites after 1 h incubation liver microsomes system. Finally, tacrine-trolox low vivo im administration rats potential penetrate across blood-brain barrier. All outstanding vitro results combination promising outcomes highlighted derivative 7u lead structure worthy further investigation.

Language: Английский

Citations

125
Curcumin in Health and Diseases: Alzheimer’s Disease and Curcumin Analogues, Derivatives, and Hybrids DOI Open Access

Eirini Chainoglou,

Dimitra Hadjipavlou–Litina

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(6), P. 1975 - 1975

Published: March 13, 2020

Worldwide, Alzheimer’s disease (AD) is the most common neurodegenerative multifactorial influencing elderly population. Nowadays, several medications, among them curcumin, are used in treatment of AD. Curcumin, which principal component Curcuma longa, has shown favorable effects forsignificantly preventing or treating During last decade, scientific community focused their research on optimization therapeutic properties and improvement pharmacokinetic curcumin. This review summarizes bibliographical data from 2009 to 2019 curcumin analogues, derivatives, hybrids, as well therapeutic, preventic, diagnostic applications Recent advances field have revealed that phenolic hydroxyl group could contribute anti-amyloidogenic activity. Phenyl methoxy groups seem suppression amyloid-β peptide (Aβ42) amyloid precursor protein (APP) andhydrophobic interactions also a growing role. Furthermore, flexible moieties, at linker, crucial for inhibition Aβ aggregation. The inhibitory activity derivatives increased with expansion aromatic rings. promising role curcumin-based compounds imaging highlighted. keto-enol tautomerism seems be novel modification design amyloid-binding agents. Molecular docking results, (Q)SAR, vitro vivo tests highlight structures chemical moieties correlated specific As result, knowledge gained existing should lead synthesis ofinnovative multitargetedcurcumin would very useful drug tools medicine both diagnosis

Language: Английский

Citations

121
Dancing with reactive oxygen species generation and elimination in nanotheranostics for disease treatment DOI
Zijian Zhou, Kaiyuan Ni, Hongzhang Deng

et al.

Advanced Drug Delivery Reviews, Journal Year: 2020, Volume and Issue: 158, P. 73 - 90

Published: Jan. 1, 2020

Language: Английский

Citations

109
Coumarin-dithiocarbamate hybrids as novel multitarget AChE and MAO-B inhibitors against Alzheimer’s disease: Design, synthesis and biological evaluation DOI
Qi He, Jing Liu, Jinshuai Lan

et al.

Bioorganic Chemistry, Journal Year: 2018, Volume and Issue: 81, P. 512 - 528

Published: Sept. 11, 2018

Language: Английский

Citations

90
High molecular weight amyloid β 1‐42 oligomers induce neurotoxicity via plasma membrane damage DOI Creative Commons

Taro Yasumoto,

Yusaku Takamura, Mayumi Tsuji

et al.

The FASEB Journal, Journal Year: 2019, Volume and Issue: 33(8), P. 9220 - 9234

Published: May 13, 2019

Amyloid β-protein (Aβ) molecules tend to aggregate and subsequently form low MW (LMW) oligomers, high (HMW) aggregates such as protofibrils, ultimately fibrils. These Aβ species can generally amyloid plaques implicated in the neurodegeneration of Alzheimer disease (AD), but therapies designed reduce plaque load have not demonstrated clinical efficacy. Recent evidence implicates oligomers AD neuropathology, precise mechanisms are uncertain. We examined neuronal dysfunction from HMW-Aβ1-42 exposure by measuring membrane integrity, reactive oxygen (ROS) generation, lipid peroxidation, fluidity, intracellular calcium regulation, passive electrophysiological properties, long-term potentiation (LTP). disturbed integrity inducing ROS generation resulting decreased dysregulation, depolarization, impaired LTP. The damaging effects were significantly greater than those LMW-Aβ1-42. Therapeutic reduction may prevent progression ameliorating direct damage.-Yasumoto, T., Takamura, Y., Tsuji, M., Watanabe-Nakayama, Imamura, K., Inoue, H., Nakamura, S., Kimura, A., Yano, Nishijo, Kiuchi, Teplow, D. B., Ono, K. High molecular weight β1-42 induce neurotoxicity via plasma damage.

Language: Английский

Citations

90
Multitarget Therapeutic Strategies for Alzheimer’s Disease: Review on Emerging Target Combinations DOI Creative Commons
Samuele Maramai, Mohamed Benchekroun, Moustafa T. Gabr

et al.

BioMed Research International, Journal Year: 2020, Volume and Issue: 2020, P. 1 - 27

Published: July 3, 2020

Neurodegenerative diseases represent nowadays one of the major health problems. Despite efforts made to unveil mechanism leading neurodegeneration, it is still not entirely clear what triggers this phenomenon and allows its progression. Nevertheless, accepted that neurodegeneration a consequence several detrimental processes, such as protein aggregation, oxidative stress, neuroinflammation, finally resulting in loss neuronal functions. Starting from these evidences, there has been wide search for novel agents able address more than single event at same time, so-called multitarget-directed ligands (MTDLs). These compounds originated combination different pharmacophoric elements which endowed them with ability interfere enzymatic and/or receptor systems, or exert neuroprotective effects by modulating proteins metal homeostasis. MTDLs have focus latest strategies discover new treatment Alzheimer’s disease (AD), considered most common form dementia characterized cognitive dysfunctions. This review aimed collecting interesting target combinations AD, detailed discussion on favorable vitro properties optimized structures already assessed vivo animal models dementia.

Language: Английский

Citations

90
Peptide‐Functionalized Prussian Blue Nanomaterial for Antioxidant Stress and NIR Photothermal Therapy against Alzheimer's Disease DOI
Xiaolei Song, Qin Ding, Wei Wei

et al.

Small, Journal Year: 2023, Volume and Issue: 19(41)

Published: June 15, 2023

Excessive accumulations of reactive oxygen species (ROS) and amyloid-β (Aβ) protein are closely associated with the complex pathogenesis Alzheimer's disease (AD). Therefore, approaches that synergistically exert elimination ROS dissociation Aβ fibrils effective therapeutic strategies for correcting AD microenvironment. Herein, a novel near infrared (NIR) responsive Prussian blue-based nanomaterial (PBK NPs) is established excellent antioxidant activity photothermal effect. PBK NPs possess similar activities to multiple enzymes, including superoxide dismutase, peroxidase, catalase, which can eliminate massive relieve oxidative stress. Under NIR irradiation, generate local heat disaggregate efficiently. By modifying CKLVFFAED peptide, display obvious targeting ability blood-brain barrier penetration binding. Furthermore, in vivo studies demonstrate have outstanding decompose plaques alleviate neuroinflammation mouse model. Overall, provide evident neuroprotection by reducing levels regulating deposition, may accelerate development multifunctional nanomaterials delaying progression AD.

Language: Английский

Citations

31