1,721,181 research outputs found
DESIGN, SYNTHESIS AND BIOCHEMICAL CHARACTERIZATION OF INHIBITORS OF PROTEIN KINASES
Full text linkThe work described in this thesis is dealing with the identification and characterization of some new potent inhibitors of protein kinases CK1 and CK2.
Four distinct sub-projects have been carried out.
In the first part some derivatives of ellagic acid, a powerful recently discovered CK2 inhibitor, have been synthesized with the aim of simplifying the ellagic acid structure composed of two condensed coumarins. Particular attention was dedicated to urolithin A, a bio-active metabolite of ellagic acid, proved to be also effective on CK2 especially after the introduction of a bromine or of a nitro group at position 4, leading to a very high efficiency in the low nanomolar range.
In the second part a series of polyiodinated benzimidazoles has been investigated for both inhibitory power and selectivity toward protein kinase CK2. The results show that 4,5,6,7-tetraiodobenzimidazoles display in general one order of magnitude lower IC50 values as compared with their tetrabrominated analogs. Molecular modeling supports the experimental data showing that the presence of iodine atoms as substituents of the benzene moiety leads to a better filling of the nucleotide binding pocket of the kinase.
The third sub-project, investigated the potency and selectivity of a newly identified anthraquinone, quinalizarin, as an inhibitor of CK2 proved to be more potent and selective than emodin. Besides a very good efficiency, with a KI value of approx. 50 nM, especially remarkable is the ability of quinalizarin to discriminate between CK2 and a number of other kinases, notably DYRK1a, PIM 1,2, e 3, HIPK2, MNK1, ERK8 and PKD1 which conversely tend to be often inhibited as drastically as CK2 by other known CK2 inhibitors.
Finally protein kinase CK1 was also taken in consideration with the aim of identifying new compounds able to selectively inhibit the different isoforms of this protein kinase.
In this case we have identified two anthraquinones proved to be among the most potent and selective inhibitors of the CK1δ isoform. Activity assays performed on different isoforms of CK1 as well as on a number of other protein kinases demonstrated high selectivity toward isoform δ and a potency comparable to that of other commercially available CK1 inhibitors.In questo elaborato viene descritta l’identificazione e la caratterizzazione di alcuni nuovi potenti inibitori di CK1 e di CK2.
Sono stati sviluppati quattro distinti sotto progetti.
Con l’obiettivo di pervenire a una semplificazione strutturale, nella prima parte sono stati sintetizzati alcuni derivati dell’acido ellagico, un inibitore di CK2 da noi recentemente identificato la cui struttura ricorda quella di due cumarine condensate.
Particolare attenzione è stata rivolta all’urolitina A, uno dei metaboliti bio-attivi dell’acido ellagico che pure è risultata efficace contro la CK2 specialmente dopo l’introduzione di un atomo di bromo o di un nitro gruppo in posizione 4 che riportano le costanti di inibizione nel basso nano molare. Nella seconda parte sono stati studiati una serie di derivati poliiodinati del benzoimidazolo sia in relazione alla loro efficacia che alla selettività. I risultati mostrano che i 4,5,6,7-tetraiodobenzimidazoli sono in genere di un ordine di grandezza più potenti rispetto ai loro analoghi tetrabromoderivati. Dati ottenuti con tecniche di modellistica molecolare mostrano che la struttura del tetraiodobenzimidazolo si colloca meglio, all’interno della tasca nucleotidica della chinasi riempiendola più efficacemente, rispetto ai corrispondenti tetrabromo e tetracloro derivati.
Nella terza parte, si è studiata l’efficacia e la selettività di un nuovo antrachinone identificato con un approccio di virtual screening, la quinalizarina, che si è rivelato più potente e selettivo della emodina. Oltre a un potere inibitorio ottimale, con una KI circa uguale a 50 nM, particolarmente interessante è l’abilità della chinalizarina di discriminare tra CK2 e un numero di chinasi, tra cui DYRK1a, PIM 1,2, e 3, HIPK2, MNK1, ERK8 e PKD1, che di solito tendono ad essere inibite altrettanto efficacemente dai più comuni inibitori di CK2.
Infine è stato svolto un lavoro anche sulla protein chinasi CK1 con l’obiettivo di individuare nuovi composti capaci di inibire selettivamente le diverse isoforme di questa protein chinasi.
Abbiamo così individuato due nuovi antrachinoni come nuovi potenziali inibitori di CK1δ. Con saggi di attività sulle diverse isoforme di CK1, così come su un discreto numero di altre protein chinasi, si è dimostrata l’alta selettività nei confronti dell’isoforma δ di CK1 e un potere inibitorio simile ai migliori inibitori di CK1 presenti in commercio
Natural and Synthetic Phosphodiesterase Inhibitors in 2023: an Update on the Impact on Neurological and Psychiatric Conditions
No full text: This Perspective provides an updated overview on the involvement of phosphodiesterase (PDE) isoforms and of the corresponding inhibitors in neurological disorders, including dementia, Parkinson's disease, multiple sclerosis, neuropsychiatric conditions and cerebral ischemia. Particular attention has been dedicated to natural and semi-synthetic compounds. Translation into the clinic of preclinical results, toxicity profile and bioavailability represent the challenging aspects in the development of PDE inhibitors. With the aim of providing the latest updates to the reader, the 2023 contributions in the field were considered for the preparation of this Perspective
Coelectrodeposition of Ternary Mn-Oxide/Polypyrrole Composites for ORR Electrocatalysts: A Study Based on Micro-X-ray Absorption Spectroscopy and X-ray Fluorescence Mapping
No full textLow energy X-ray fluorescence (XRF) and soft X-ray absorption (XAS)
microspectroscopies at high space-resolution are employed for the investigation of the
coelectrodeposition of composites consisting of a polypyrrole(PPy)-matrix and Mn-based
ternary dispersoids, that have been proposed as promising electrocatalysts for
oxygen-reduction electrodes. Specifically, we studied Mn–Co–Cu/PP, Mn–Co–Mg/PPy
and Mn–Ni–Mg/PPy co-electrodeposits. The Mn–Co–Cu system features the best ORR
electrocatalytic activity in terms of electron transfer number, onset potential, half-wave
potential and current density. XRF maps and micro-XAS spectra yield compositional
and chemical state distributions, contributing unique molecular-level information on
the pulse-plating processes. Mn, Ni, Co and Mg exhibit a bimodal distribution consisting
of mesoscopic aggregates of micrometric globuli, separated by polymer-rich ridges. Within
this common qualitative scenario, the individual systems exhibit quantitatively different
chemical distribution patterns, resulting from specific electrokinetic and electrosorption
properties of the single components. The electrodeposits consist of Mn3+,4+-oxide particles,
accompanied by combinations of Co0/Co2+, Ni0/Ni2+ and Cu0,+/Cu2+ resulting from the alternance of cathodic and anodic pulses. The formation of highly electroactive Mn3+,4+ in
the as-fabricated material is a specific feature of the ternary systems, deriving from
synergistic stabilisation brought about by two types of bivalent dopants as well as by
galvanic contact to elemental metal; this result represents a considerable improvement in
material quality with respect to previously studied Mn/PPy and Mn-based/PPy binaries
Fentanyl–Antibody Interaction as a Novel Strategy against Opiates and Opioids Abuse
No full textWhile naloxone remains the antidote for opioid overdoses, more efficient tools are required to effectively combat this growing crisis. Vaccines and antibodies targeting substances of abuse appear to be a novel and promising approach to tackling the fentanyl and opioid epidemic. After an initial in-depth rundown on the pharmacodynamics of the substances involved from a structural and mechanistic standpoint, and a brief overview of pharmacological approaches used in clinical settings for managing overdoses and opioid addiction, this Perspective will be mainly focused on these innovative strategies, based on the development of antibodies binding and sequestering substances of abuse and on their generation in vivo through vaccines. The most promising approaches will be examined, from production techniques to their potential clinical applications, analyzing the structures and mechanisms of antibody-substance interactions and comparing these with receptor binding processes
An Updated Overview on the Role of Small Molecules and Natural Compounds in the “Young Science” of Rejuvenation
No full textAging is a gradual process that occurs over time which leads to a progressive decline of cells and tissues. Telomere shortening, genetic instability, epigenetic alteration, and the accumulation of misfolded proteins represent the main hallmarks that cause perturbed cellular functions; this occurs in conjunction with the progression of the so-called “aging clocks”. Rejuvenation aims to influence the natural evolution of such aging clocks and to enhance regenerative capacity, thus overcoming the limitations of common anti-aging interventions. Current rejuvenation processes are based on heterochronic parabiosis, cell damage dilution through asymmetrical cell division, the excretion of extracellular vesicles, the modulation of genetic instability involving G-quadruplexes and DNA methylation, and cell reprogramming using Yamanaka factors and the actions of antioxidant species. In this context, we reviewed the most recent contributions that report on small molecules acting as senotherapeutics; these molecules act by promoting one or more of the abovementioned processes. Candidate drugs and natural compounds that are being studied as potential rejuvenation therapies act by interfering with CDGSH iron-sulfur domain 2 (CISD2) expression, G-quadruplex structures, DNA methylation, and mitochondrial decay. Moreover, direct and indirect antioxidants have been reported to counteract or revert aging through a combination of mixed mechanisms
Therapeutic Potential of Phosphodiesterase (PDE) Inhibitors Against Neurodegeneration: the Perspective of the Medicinal Chemist
No full textElectrodeposition and Ageing of Mn-Based Binary Composite Oxygen Reduction Reaction Electrocatalysts
No full textElectrodeposition and ageing under oxygen reduction reaction (ORR) of Mn-X/PPy (X=Co, Mg, Ni; PPy=polypyrrole) and Mn-Ag/G (G=graphene) composite electrocatalysts have been studied by quasi-in-situ soft X-ray absorption and fluorescence microspectroscopy. The fabricated materials exhibit micro-grained morphologies in which Mn is present mainly as Mn2+, accompanied by combinations of Co0/Co2+ and Ni0/Ni2+. Ageing leads to the formation of progressively larger mesoscopic aggregates. Initial ageing yields more active Mn3+ and Mn4+, in agreement with an improved ORR behaviour. Prolonged ageing causes the loss of Mn3+ and Mn4+ from the surface, in correlation with a degradation of the ORR response. In the investigated ageing period, Mn-Mg/PPy exhibits the best durability, with about half of the catalyst grains still showing the presence of Mn3+/Mn4+, while the others consist mainly of Mn2+. In Mn-Ni/PPy, the Ni2+ content tends to increase with ageing whereas Co3+ forms in the Mn-Co/PPy composites
Mechanistic investigation on compounds from Amorpha fruticosa L. targeting acetylcholinesterase
No full textAcetylcholinesterase (AChE) is the enzyme targeted by drugs used for the symptomatic treatment of cognitive decline associated with Alzheimer’s disease. While in vitro data suggest the AChE inhibitory potential of A. fruticosa extracts and components such as rotenoids, in-depth mechanistic investigations are missing. A wide array of computational techniques, including ligand-based approaches, molecular docking, molecular dynamics, and machine learning-assisted toxicity prediction were enrolled in the current study, highlighting the rotenoid 6α,12α-dehydrodeguelin as a promising lead for the development of AChE inhibitors
Therapeutic Approaches Interfering with Nuclear Localization Signals: An Emerging Strategy for CNS-Related Diseases
No full textAlthough medicinal chemistry is constantly looking for new therapeutic approaches against pathological conditions affecting the central nervous system (CNS), such as neurodegeneration and cancer, this quest has not been fully successful yet. The lack of understanding of all the complex mechanisms underlying these conditions makes the identification of new effective drugs challenging. A wide variety of pathophysiological events are regulated at both nuclear and cytoplasmic levels, and in this context, targeting the shuttle system composed of the karyopherin superfamily and their cargoes may provide an alternative strategy. Molecular recognition is highly specific and strictly related to the presence of special “tag” regions, known as nuclear localization signals, that are localized in the amino acid sequences of cargoes. Importantly, their trafficking is involved in various pathophysiological processes, including CNS diseases. Curiously, although this system has been studied intensively, much remains to be discovered to date. Throughout the years, drug discovery allowed the identification of small molecules and peptides able to target karyopherin-cargo complexes to provide new potential pharmacological treatments. Indeed, the first examples of drug candidates targeting this mechanism that reached clinical trials are appearing in the literature. With this mini-review, this study aims at presenting an updated overview on the most recent reports investigating the use of the karyopherin shuttle system as a new therapeutic target especially for CNS-related diseases
Electrochemical reconstruction of a heavily corroded Tarentum hemiobolus silver coin
No full textIn this paper we report on the electrochemical reconstruction of a Tarentum hemiobolus Ag coin, severely corroded in marine environment. As assessed by conventional analytical tools, most of the initially metallic Ag coin had been converted to AgCl by exposure to the aggressive coastal burial conditions. X-ray computed microtomography proved that only small portions of the artefact had preserved their metallic nature. Since the engraving was preserved partly in the corrosion product bulk and partly in the metallic rests, electrodeposition of Ag from the AgCl layer, under controlled conditions ensuring shape preservation, resulted in the reconstruction of the coin surface with full recovery of the original engraving. Such optimal electrodeposition conditions were identified by a combination of electrochemical and quasi-in situ X-ray microtomography experiments, carried out with artificially corrored engraved Ag wires. Microtomography of the reconstructed coin confirmed the compaction of the external Ag layer and disclosed that the central core of the coin still contains unconverted AgCl. The presence of such a mineralised core does not however impact the numismatic use of the coin and the safeguard of the original engraving
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