DNA-interacting properties of two analogous square-planar cis-chlorido complexes: copper versus palladium

Marcos V. Palmeira-Mello, Ana B. Caballero, Aida Lopez-Espinar, Guilherme P. Guedes, Amparo Caubet, Alessandra M. Teles de Souza, Mauricio Lanznaster and Patrick Gamez 

J. Biol. Inorg. Chem. 2021, 26, 727-740.

Two square-planar coordination compounds, namely [Cu(CPYA)Cl2] (1) and [Pd(CPYA)Cl2] (2), were prepared from the ligand 4-chloro-N-(pyridin-2-ylmethyl)aniline (CPYA) and two chloride salts, and were fully characterized, including by X-ray diffraction. Spectroscopic, electrophoretic and AFM studies revealed that the two isostructural compounds were interacting differently with DNA. In both cases, the initial interaction involves electrostatic contacts of the CPYA ligand in the minor groove (as suggested by molecular docking), but subsequent strong binding occurs with the palladium(II) complex 2, whereas the binding with the copper complex 1 is weaker and concentration dependent. The strong binding of 2 eventually leads to the cleavage of the double strand and the redox activity of 1 allows to oxidatively cleave the biomolecule.

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Dual Inhibitors of Amyloid-beta and Tau Aggregation with Amyloid-beta Disaggregating Properties: Extended In Cellulo, In Silico, and Kinetic Studies of Multifunctional Anti-Alzheimer's Agents

Anna Pasieka, Dawid Panek, Natalia Szalaj, Alba Espargaró, Anna Wieckowska, Barbara Malawska, Raimon Sabate and Bajda Marek

ACS Chem. Neurosci. 2021, 12, 2057-2068.

In Alzheimer’s disease, neurons slowly degenerate due to the accumulation of misfolded amyloid β and tau proteins. In our research, we performed extended studies directed at amyloid β and tau aggregation inhibition using in cellulo (Escherichia coli model of protein aggregation), in silico, and in vitro kinetic studies. We tested our library of 1-benzylamino-2-hydroxyalkyl multifunctional anti-Alzheimer’s agents and identified very potent dual aggregation inhibitors. Among the tested derivatives, we selected compound 18, which exhibited a unique profile of biological activity. This compound was the most potent and balanced dual aggregation inhibitor (Aβ42 inhibition (inh.) 80.0%, tau inh. 68.3% in 10 μM), with previously reported in vitro inhibitory activity against hBuChE, hBACE1, and Aβ (hBuChE IC50 = 5.74 μM; hBACE1 IC50 = 41.6 μM; Aβ aggregation (aggr.) inh. IC50 = 3.09 μM). In docking studies for both proteins, we tried to explain the different structural requirements for the inhibition of Aβ vs tau. Moreover, docking and kinetic studies showed that compound 18 could inhibit the amyloid aggregation process at several steps and also displayed disaggregating properties. These results may help to design the next generations of dual or selective aggregation inhibitors.

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Piano-Stool Ruthenium(II) Complexes with Delayed Cytotoxic Activity: Origin of the Lag Time

Laia Rafols, Dana Josa, David Aguilà, Leoní A. Barrios, Olivier Roubeau, Jordi Cirera, Vanessa Soto-Cerrato, Ricardo Pérez-Tomás, Manuel Martínez, Arnald Grabulosa, and Patrick Gamez

Inorg. Chem. 2021, 60, 7974-7990.

We have recently reported a series of piano-stool ruthenium(II) complexes of the general formula [RuCl2(η6-arene)(P(1-pyrenyl)R2R3)] showing excellent cytotoxic activities (particularly when R2 = R3 = methyl). In the present study, new members of this family of compounds have been prepared with the objective to investigate the effect of the steric hindrance of a bulky phosphane ligand, namely diisopropyl(1-pyrenyl)phosphane (L), on exchange reactions involving the coordinated halides (X = Cl, I). Two η6-arene rings were used, i.e. η6-methyl benzoate (mba) and η6-p-cymene (p-cym), and four complexes were synthesized, namely [RuCl2(mba)(L)] (1Cl2iPr), [RuI2(mba)(L)] (1I2iPr), [RuCl2(p-cym)(L)] (2Cl2iPr), and [RuI2(p-cym)(L)] (2I2iPr). Unexpectedly, all of the complexes exhibited poor cytotoxic activities after 24 h of incubation with cells, in contrast to the related compounds previously reported. However, it was observed that aged DMSO solutions of 2I2iPr (from 2 to 7 days) exhibited better activities in comparison to freshly prepared solutions and that the activity improved over “aging” time. Thorough studies were therefore performed to uncover the origin of this lag time in the cytotoxicity efficiency. The data achieved clearly demonstrated that compounds 2I2iPr and 2Cl2iPr were undergoing a series of transformation reactions in DMSO (with higher rates for the iodido complex 2I2iPr), ultimately generating cyclometalated species through a mechanism involving DMSO as a coordinated proton abstractor. The cyclometalated complexes detected in solution were subsequently prepared; hence, pure [RuCl(p-cym)(κ2C-diisopropyl(1-pyrenyl)phosphane)] (3CliPr), [RuI(p-cym)(κ2C-diisopropyl(1-pyrenyl)phosphane)] (3IiPr), and [Ru(p-cym)(κS-dmso)(κ2C-diisopropyl(1-pyrenyl)phosphane)]PF6 (3dmsoiPr) were synthesized and fully characterized. Remarkably, 3CliPr, 3IiPr, and 3dmsoiPr are all very efficient cytotoxic agents, exhibiting slightly better activities in comparison to the chlorido noncyclometalated complexes [RuCl2(η6-arene)(P(1-pyrenyl)R2R3)] described in an earlier report. For comparison purposes, the iodido compounds [RuI2(mba)(dimethyl(1-pyrenyl)phosphane)] (1I2Me) and [RuI2(p-cym)(dimethyl(1-pyrenyl)phosphane)] (2I2Me), bearing the less hindered dimethyl(1-pyrenyl)phosphane ligand, have also been prepared. The cytotoxic and chemical behaviors of 1I2Me and 1I2Me were comparable to those of their chlorido counterparts reported previously.

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Azobioisosteres of Curcumin with Pronounced Activity against Amyloid Aggregation, Intracellular Oxidative Stress, and Neuroinflammation

Julian Hofmann, Tiziana Ginex, Alba Espargaró, Matthias Scheiner, Sandra Gunesch, Marc Aragó, Christian Stigloher, Raimon Sabate, F. Javier Luque, Michael Decker, and Joan Estelrich

Chem. Eur. J. 2021, 27, 6015-6027.

Many (poly‐)phenolic natural products, for example, curcumin and taxifolin, have been studied for their activity against specific hallmarks of neurodegeneration, such as amyloid‐β 42 (Aβ42) aggregation and neuroinflammation. Due to their drawbacks, arising from poor pharmacokinetics, rapid metabolism, and even instability in aqueous medium, the biological activity of azobenzene compounds carrying a pharmacophoric catechol group, which have been designed as bioisoteres of curcumin has been examined. Molecular simulations reveal the ability of these compounds to form a hydrophobic cluster with Aβ42, which adopts different folds, affecting the propensity to populate fibril‐like conformations. Furthermore, the curcumin bioisosteres exceeded the parent compound in activity against Aβ42 aggregation inhibition, glutamate‐induced intracellular oxidative stress in HT22 cells, and neuroinflammation in microglial BV‐2 cells. The most active compound prevented apoptosis of HT22 cells at a concentration of 2.5 μM (83 % cell survival), whereas curcumin only showed very low protection at 10 μM (21 % cell survival). 

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Dual Effect of Prussian Blue Nanoparticles on Aβ40 Aggregation: β-Sheet Fibril Reduction and Copper Dyshomeostasis Regulation

Joanna Kowalczyk, Ettore Grapsi, Alba Espargaró, Ana B. Caballero, Jordi Juárez-Jiménez, Maria A. Busquets, Patrick Gamez, Raimon Sabate, and Joan Estelrich

Biomacromolecules 2021, 22, 430-40.

Alzheimer's disease (AD), affecting almost 50 million individuals worldwide, is currently the first cause of dementia. Despite the tremendous research efforts in the last decade, only four supportive or palliative drugs, namely, acetylcholinesterase (AChE) inhibitors donepezil, galantamine, and rivastigmine and the glutamate NMDA receptor antagonist memantine, are currently available. New therapeutic strategies are becoming prominent, such as the direct inhibition of amyloid formation or the regulation of metal homeostasis. In the present report, the potential use of Prussian blue (PB), a drug that is in the World Health Organization Model List of Essential Medicines, in AD treatment is demonstrated. Both in vitro and in cellulo studies indeed suggest that PB nanoparticles (PBNPs) are capable of reducing the formation of typical amyloid-β fibers (detected by thioflavin T fluorescence) and restoring the usual amyloid fibrillation pathway via chelation/sequestration of copper, which is found in high concentrations in senile plaques. 

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Nanochaperone-based strategies to control protein aggregation linked to conformational diseases

Ana B. Caballero, Patrick Gamez

Angew. Chem. Int. Ed. 2021, 60, 41-52.

The generation of highly organized amyloid fibrils is associated with a wide range  of conformational  pathologies, including primarily neurodegenerative diseases. Such disorders are characterized by misfolded proteins that lose their normal physiological roles and acquire toxicity. Recent findings suggest that proteostasis network impairment may be one of the causes leading to the accumulation and spread of amyloids. These observations are certainly contributing to a new focus in anti-amyloid drug design, whose efforts are so far being centered on single-target approaches aimed at inhibiting amyloid aggregation. Chaperones, known to maintain proteostasis, hence represent interesting targets for  the development of novel therapeutics owing to their potential protective role against protein misfolding diseases. In this minireview, research on nanoparticles that can either emulate or help molecular chaperones in recognizing and/or correcting protein misfolding is discussed. The nascent concept of "nanochaperone" may indeed set future directions towards the development of cost-effective, disease-modifying drugs to treat several currently fatal disorders.

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Air Curtains Equipped With Hydroalcoholic Aerosol Sprayers for Massive COVID-19 Disinfection

Judit Raventos, Raimon Sabate

Front. Public Health 2021, 8, 582782.

Coronavirus disease 2019 (COVID-19) affects thousands of healthcare workers in Europe. Latestfigures show that healthcare workers represent up to 9 and 14% of Italy’s and Spain’s COVID-19 cases, respectively. In China, more than 3,300 healthcare workers have been contaminated(1,2). Better protection for healthcare workers is clearly required. High levels of COVID-19contamination in specialist wards and intensive care units and of equipment (from keyboards to gelhand sanitizers) indicate that the measures currently taken to control COVID-19 are insufficient,especially in hospital centers where a large number of infections occur and where the mostvulnerable population is found.

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