Publications by authors named "Michela Rosini"

66 Publications

NRF2 and PPAR-γ Pathways in Oligodendrocyte Progenitors: Focus on ROS Protection, Mitochondrial Biogenesis and Promotion of Cell Differentiation.

Int J Mol Sci 2020 Sep 29;21(19). Epub 2020 Sep 29.

National Center for Research and Preclinical and Clinical Evaluation of Drugs, Istituto Superiore di Sanità, 00161 Rome, Italy.

An adequate protection from oxidative and inflammatory reactions, together with the promotion of oligodendrocyte progenitor (OP) differentiation, is needed to recover from myelin damage in demyelinating diseases. Mitochondria are targets of inflammatory and oxidative insults and are essential in oligodendrocyte differentiation. It is known that nuclear factor-erythroid 2-related factor/antioxidant responsive element (NRF2/ARE) and peroxisome proliferator-activated receptor gamma/PPAR-γ response element (PPAR-γ/PPRE) pathways control inflammation and overcome mitochondrial impairment. In this study, we analyzed the effects of activators of these pathways on mitochondrial features, protection from inflammatory/mitochondrial insults and cell differentiation in OP cultures, to depict the specificities and similarities of their actions. We used dimethyl-fumarate (DMF) and pioglitazone (pio) as agents activating NRF2 and PPAR-γ, respectively, and two synthetic hybrids acting differently on the NRF2/ARE pathway. Only DMF and compound 1 caused early effects on the mitochondria. Both DMF and pio induced mitochondrial biogenesis but different antioxidant repertoires. Moreover, pio induced OP differentiation more efficiently than DMF. Finally, DMF, pio and compound 1 protected from tumor necrosis factor-alpha (TNF-α) insult, with pio showing faster kinetics of action and compound 1 a higher activity than DMF. In conclusion, NRF2 and PPAR-γ by inducing partially overlapping pathways accomplish complementary functions aimed at the preservation of mitochondrial function, the defense against oxidative stress and the promotion of OP differentiation.
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http://dx.doi.org/10.3390/ijms21197216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583077PMC
September 2020

Targeting Cytokine Release Through the Differential Modulation of Nrf2 and NF-κB Pathways by Electrophilic/Non-Electrophilic Compounds.

Front Pharmacol 2020 14;11:1256. Epub 2020 Aug 14.

Department of Drug Sciences, Pharmacology Section, University of Pavia, Pavia, Italy.

The transcription factor Nrf2 coordinates a multifaceted response to various forms of stress and to inflammatory processes, maintaining a homeostatic intracellular environment. Nrf2 anti-inflammatory activity has been related to the crosstalk with the transcription factor NF-κB, a pivotal mediator of inflammatory responses and of multiple aspects of innate and adaptative immune functions. However, the underlying molecular basis has not been completely clarified. By combining into new chemical entities, the hydroxycinnamoyl motif from curcumin and the allyl mercaptan moiety of garlic organosulfur compounds, we tested a set of molecules, carrying (pro)electrophilic features responsible for the activation of the Nrf2 pathway, as valuable pharmacologic tools to dissect the mechanistic connection between Nrf2 and NF-κB. We investigated whether the activation of the Nrf2 pathway by (pro)electrophilic compounds may interfere with the secretion of pro-inflammatory cytokines, during immune stimulation, in a human immortalized monocyte-like cell line (THP-1). The capability of compounds to affect the NF-κB pathway was also evaluated. We assessed the compounds-mediated regulation of cytokine and chemokine release by using Luminex X-MAP technology in human primary peripheral blood mononuclear cells (PBMCs) upon LPS stimulation. We found that all compounds, also in the absence of electrophilic moieties, significantly suppressed the LPS-evoked secretion of pro-inflammatory cytokines such as TNFα and IL-1β, but not of IL-8, in THP-1 cells. A reduction in the release of pro-inflammatory mediators similar to that induced by the compounds was also observed after siRNA mediated-Nrf2 knockdown, thus indicating that the attenuation of cytokine secretion cannot be directly ascribed to the activation of Nrf2 signaling pathway. Moreover, all compounds, with the exception of compound 1, attenuated the LPS-induced activation of the NF-κB pathway, by reducing the upstream phosphorylation of IκB, the NF-κB nuclear translocation, as well as the activation of NF-κB promoter. In human PBMCs, compound 4 and CURC attenuated TNFα release as observed in THP-1 cells, and all compounds acting as Nrf2 inducers significantly decreased the levels of MCP-1/CCL2, as well as the release of the pro-inflammatory cytokine IL-12. Altogether, the compounds induced a differential modulation of innate immune cytokine release, by differently regulating Nrf2 and NF-κB intracellular signaling pathways.
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http://dx.doi.org/10.3389/fphar.2020.01256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456937PMC
August 2020

Memantine Derivatives as Multitarget Agents in Alzheimer's Disease.

Molecules 2020 Sep 2;25(17). Epub 2020 Sep 2.

Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.

Memantine (3,5-dimethyladamantan-1-amine) is an orally active, noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist approved for treatment of moderate-to-severe Alzheimer's disease (AD), a neurodegenerative condition characterized by a progressive cognitive decline. Unfortunately, memantine as well as the other class of drugs licensed for AD treatment acting as acetylcholinesterase inhibitors (AChEIs), provide only symptomatic relief. Thus, the urgent need in AD drug development is for disease-modifying therapies that may require approaching targets from more than one path at once or multiple targets simultaneously. Indeed, increasing evidence suggests that the modulation of a single neurotransmitter system represents a reductive approach to face the complexity of AD. Memantine is viewed as a privileged NMDAR-directed structure, and therefore, represents the driving motif in the design of a variety of multi-target directed ligands (MTDLs). In this review, we present selected examples of small molecules recently designed as MTDLs to contrast AD, by combining in a single entity the amantadine core of memantine with the pharmacophoric features of known neuroprotectants, such as antioxidant agents, AChEIs and Aβ-aggregation inhibitors.
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http://dx.doi.org/10.3390/molecules25174005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504780PMC
September 2020

-Light on Age-Related Macular Degeneration: Targeting Nrf2-Pathway as a Novel Therapeutic Strategy for Retinal Pigment Epithelium.

Front Pharmacol 2020 5;11:844. Epub 2020 Jun 5.

Section of Pharmacology, Department of Drug Sciences, University of Pavia, Pavia, Italy.

Age-related macular degeneration (AMD) is a common disease with a multifactorial aetiology, still lacking effective and curative therapies. Among the early events triggering AMD is the deterioration of the retinal pigment epithelium (RPE), whose fundamental functions assure good health of the retina. RPE is physiologically exposed to high levels of oxidative stress during its lifespan; thus, the integrity and well-functioning of its antioxidant systems are crucial to maintain RPE homeostasis. Among these defensive systems, the Nrf2-pathway plays a primary role. Literature evidence suggests that, in aged and especially in AMD RPE, there is an imbalance between the increased pro-oxidant stress, and the impaired endogenous detoxifying systems, finally reverberating on RPE functions and survival. In this study on wild type (WT) and Nrf2-silenced (siNrf2) ARPE-19 cells exposed to various AMD-related (HO, 4-HNE, MG132 + Bafilomycin), we show that the Nrf2-pathway activation is a physiological protective stress response, leading downstream to an up-regulation of the Nrf2-targets HO1 and p62, and that a Nrf2 impairment predisposes the cells to a higher vulnerability to stress. In search of new pharmacologically active compounds potentially useful for AMD, four nature-inspired hybrids (NIH) were individually characterized as Nrf2 activators, and their pharmacological activity was investigated in ARPE-19 cells. The Nrf2 activator dimethyl-fumarate (DMF; 10 μM) was used as a positive control. Three out of the four tested NIH (5 μM) display both direct and indirect antioxidant properties, in addition to cytoprotective effects in ARPE-19 cells under pro-oxidant stimuli. The observed pro-survival effects require the presence of Nrf2, with the exception of the lead compound NIH1, able to exert a still significant, albeit lower, protection even in siNrf2 cells, supporting the concept of the existence of both Nrf2-dependent and independent pathways mediating pro-survival effects. In conclusion, by using some pharmacological tools as well as a reference compound, we dissected the role of the Nrf2-pathway in ARPE-19 stress response, suggesting that the Nrf2 induction represents an efficient defensive strategy to prevent the stress-induced damage.
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http://dx.doi.org/10.3389/fphar.2020.00844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291861PMC
June 2020

Functionalized Cannabinoid Subtype 2 Receptor Ligands: Fluorescent, PET, Photochromic and Covalent Molecular Probes.

ChemMedChem 2020 08 24;15(15):1374-1389. Epub 2020 Jun 24.

Pharmaceutical and Medicinal Chemistry Institute of Pharmacy and Food Chemistry, Julius Maximilian University of Würzburg, Am Hubland, 97074, Würzburg, Germany.

Cannabinoid subtype 2 receptors (CB Rs) are G protein-coupled receptors (GPCRs) belonging to the endocannabinoid system, a complex network of signalling pathways leading to the regulation of key physiological processes. Interestingly, CB Rs are strongly up-regulated in pathological conditions correlated with the onset of inflammatory events like cancer and neurodegenerative diseases. Therefore, CB Rs represent an important biological target for therapeutic as well as diagnostic purposes. No CB R-selective drugs are yet on the market, thus underlining a that deeper comprehension of CB Rs' complex activation pathways and their role in the regulation of diseases is needed. Herein, we report an overview of pharmacological and imaging tools such as fluorescent, positron emission tomography (PET), photochromic and covalent selective CB R ligands. These molecular probes can be used in vitro as well as in vivo to investigate and explore the unravelled role(s) of CB Rs, and they can help to design suitable CB R-targeted drugs.
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http://dx.doi.org/10.1002/cmdc.202000298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497013PMC
August 2020

Modulation of Keap1/Nrf2/ARE Signaling Pathway by Curcuma- and Garlic-Derived Hybrids.

Front Pharmacol 2019 28;10:1597. Epub 2020 Jan 28.

Department of Drug Sciences, University of Pavia, Pavia, Italy.

Nrf2 is a basic leucine zipper transcription factor that binds to the promoter region of the antioxidant response element (ARE), inducing the coordinated up-regulation of antioxidant and detoxification genes. We recently synthesized a set of new molecules by combining the functional moieties of curcumin and diallyl sulfide, both known to induce the expression of antioxidant phase II enzymes by activating Nrf2 pathway. The aim of the study is to investigate the ability of such compounds to activate Keap1/Nrf2/ARE cytoprotective pathway, in comparison with two reference Nrf2-activators: curcumin and dimethyl fumarate, a drug approved for the treatment of relapsing-remitting multiple sclerosis. Furthermore, since Nrf2 pathway is known to be regulated also by epigenetic modifications, including key modifications in microRNA (miRNA) expression, the effects of the hybrids on the expression levels of selected miRNAs, associated with Nrf2 signaling pathway have also been investigated. The results show that compounds exert antioxidant effect by activating Nrf2 signaling pathway and inducing the ARE-regulated expression of its downstream target genes, such as HO-1 and NQO1, with two hybrids to a higher extent than curcumin. In addition, some molecules induce changes in the expression levels of miR-125b-5p, even if to a lesser extent than curcumin. However, no changes have been observed in the expression levels of mRNA coding for glutathione synthetase, suggesting that the modulation of this mRNA is not strictly under the control of miR-125b-5p, which could be influenced by other miRNAs.
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http://dx.doi.org/10.3389/fphar.2019.01597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997134PMC
January 2020

Merging memantine and ferulic acid to probe connections between NMDA receptors, oxidative stress and amyloid-β peptide in Alzheimer's disease.

Eur J Med Chem 2019 Oct 5;180:111-120. Epub 2019 Jul 5.

Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy. Electronic address:

N-methyl-d-aspartate receptors (NMDAR) are critically involved in the pathogenesis of Alzheimer's disease (AD). Acting as an open-channel blocker, the anti-AD drug memantine preferentially targets NMDAR overactivation, which has been proposed to trigger neurotoxic events mediated by amyloid β peptide (Aβ) and oxidative stress. In this study, we applied a multifunctional approach by conjugating memantine to ferulic acid, which is known to protect the brain from Aβ neurotoxicity and neuronal death caused by ROS. The most interesting compound (7) behaved, like memantine, as a voltage-dependent antagonist of NMDAR (IC = 6.9 μM). In addition, at 10 μM concentration, 7 exerted antioxidant properties both directly and indirectly through the activation of the Nrf-2 pathway in SH-SY5Y cells. At the same concentration, differently from the parent compounds memantine and ferulic acid alone, it was able to modulate Aβ production, as revealed by the observed increase of the non-amyloidogenic sAPPα in H4-SW cells. These findings suggest that compound 7 may represent a promising tool for investigating NMDAR-mediated neurotoxic events involving Aβ burden and oxidative damage.
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http://dx.doi.org/10.1016/j.ejmech.2019.07.011DOI Listing
October 2019

Benextramine and derivatives as novel human monoamine oxidases inhibitors: an integrated approach.

FEBS J 2019 12 29;286(24):4995-5015. Epub 2019 Jul 29.

Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Italy.

The two human monoamine oxidase isoforms (namely MAO A and MAO B) are enzymes involved in the catabolism of monoamines, including neurotransmitters, and for this reason are well-known and attractive pharmacological targets in neuropsychiatric and neurodegenerative diseases, for which novel pharmacological approaches are necessary. Benextramine is a tetraamine disulfide mainly known as irreversible α-adrenergic antagonist, but able to hit additional targets involved in neurodegeneration. As the molecular structures of monoamine oxidases contain nine cysteine residues, the aim of this study was to evaluate benextramine and eleven structurally related polyamine disulfides as potential MAO inhibitors. Most of the compounds were found to induce irreversible inactivation of MAOs with inactivation potency depending on both the polyamine structure and the enzyme isoform. The more effective compounds generally showed preference for MAO B. Structure-activity relationships studies revealed the key role played by the disulfide core of these molecules in the inactivation mechanism. Docking experiments pointed to Cys323, in MAO A, and Cys172, in MAO B, as target of this type of inhibitors thus suggesting that their covalent binding inside the MAO active site sterically impedes the entrance of substrate towards the FAD cofactor. The effectiveness of benextramine in inactivating MAOs was demonstrated in SH-SY5Y neuroblastoma cell line. These results demonstrated for the first time that benextramine and its derivatives can inactivate human MAOs exploiting a mechanism different from that of the classical MAO inhibitors and could be a starting point for the development of pharmacological tools in neurodegenerative diseases.
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http://dx.doi.org/10.1111/febs.14994DOI Listing
December 2019

Controlled Iontophoretic Delivery and of ARN14140-A Multitarget Compound for Alzheimer's Disease.

Mol Pharm 2019 08 5;16(8):3460-3468. Epub 2019 Jul 5.

School of Pharmaceutical Sciences , University of Geneva and University of Lausanne , Geneva , Switzerland.

ARN14140 is a galantamine-memantine conjugate that acts upon both cholinergic and glutamatergic pathways for better management of Alzheimer's disease. Poor oral bioavailability and pharmacokinetics meant that earlier preclinical studies employed intracerebroventricular injection to administer ARN14140 directly to the brain. The aim of the present study was to evaluate the feasibility of using constant current transdermal iontophoresis for the noninvasive systemic delivery of ARN14140 and to quantify the amounts present in the blood and the brain. Preliminary experiments were performed using porcine skin and validated with human skin. Cumulative ARN14140 permeation across the skin increased linearly with current density and concentration. Delivery efficiency (i.e., fraction of the amount applied that is delivered) reached an exceptional 76.9%. Statistically equivalent delivery was observed after iontophoresis across human and porcine skin. studies in male Wistar rats showed that iontophoretic transport of ARN14140 could be controlled using the current density (426.7 ± 42 and 1118.3 ± 73 nmol/cm at 0.15 and 0.5 mA/cm for 6 h) and demonstrated that transdermal iontophoresis was able to deliver ARN14140 noninvasively to the brain. This is the first report quantifying drug levels in the blood and the brain following transdermal iontophoresis.
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http://dx.doi.org/10.1021/acs.molpharmaceut.9b00252DOI Listing
August 2019

Lights and shadows of electrophile signaling: focus on the Nrf2-Keap1 pathway.

Future Med Chem 2019 04 3;11(7):707-721. Epub 2019 Apr 3.

Department of Pharmacy & Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.

Targeted covalent modification is assuming consolidated importance in drug discovery. In this context, the electrophilic tuning of redox-dependent cell signaling is attracting major interest, as it opens prospect for treating numerous pathologic conditions. Herein, we discuss the rationale and the issues of electrophile-based approaches, focusing on the transcriptional Nrf2-Keap1 pathway as a test case. We also highlight relevant medicinal chemistry strategies researchers have devised to meet the ambitious goal, dwelling on the investigational and therapeutic potential of modulating redox-signaling networks through regulatory cysteine switches.
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http://dx.doi.org/10.4155/fmc-2018-0423DOI Listing
April 2019

Exploring the activity of polyamine analogues on polyamine and spermine oxidase: methoctramine, a potent and selective inhibitor of polyamine oxidase.

J Enzyme Inhib Med Chem 2019 Dec;34(1):740-752

d Department of Pharmacy and Biotechnology , Alma Mater Studiorum-University of Bologna , Bologna , Italy.

Fourteen polyamine analogues, asymmetric or symmetric substituted spermine (1-9) or methoctramine (10-14) analogues, were evaluated as potential inhibitors or substrates of two enzymes of the polyamine catabolic pathway, spermine oxidase (SMOX) and acetylpolyamine oxidase (PAOX). Compound 2 turned out to be the best substrate for PAOX, having the highest affinity and catalytic efficiency with respect to its physiological substrates. Methoctramine (10), a well-known muscarinic M receptor antagonist, emerged as the most potent competitive PAOX inhibitor known so far (K = 10 nM), endowed with very good selectivity compared with SMOX (K=1.2 μM vs SMOX). The efficacy of methoctramine in inhibiting PAOX activity was confirmed in the HT22 cell line. Methoctramine is a very promising tool in the design of drugs targeting the polyamine catabolism pathway, both to understand the physio-pathological role of PAOX vs SMOX and for pharmacological applications, being the polyamine pathway involved in various pathologies.
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http://dx.doi.org/10.1080/14756366.2019.1584620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407594PMC
December 2019

Immunomodulators Inspired by Nature: A Review on Curcumin and Echinacea.

Molecules 2018 Oct 26;23(11). Epub 2018 Oct 26.

Department of Drug Sciences-Pharmacology Section, University of Pavia, 27100 Pavia, Italy.

The immune system is an efficient integrated network of cellular elements and chemicals developed to preserve the integrity of the organism against external insults and its correct functioning and balance are essential to avoid the occurrence of a great variety of disorders. To date, evidence from literature highlights an increase in immunological diseases and a great attention has been focused on the development of molecules able to modulate the immune response. There is an enormous global demand for new effective therapies and researchers are investigating new fields. One promising strategy is the use of herbal medicines as integrative, complementary and preventive therapy. The active components in medical plants have always been an important source of clinical therapeutics and the study of their molecular pharmacology is an enormous challenge since they offer a great chemical diversity with often multi-pharmacological activity. In this review, we mainly analysed the immunomodulatory/antinflammatory activity of spp. and , focusing on some issues of the phytochemical research and on new possible strategies to obtain novel agents to supplement the present therapies.
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http://dx.doi.org/10.3390/molecules23112778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278270PMC
October 2018

Novel xanthone-polyamine conjugates as catalytic inhibitors of human topoisomerase IIα.

Bioorg Med Chem Lett 2017 10 8;27(20):4687-4693. Epub 2017 Sep 8.

Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA; Department of Medicine (Hematology/Oncology), Vanderbilt University School of Medicine, Nashville, TN 37232-6307, USA; VA Tennessee Valley Healthcare System, Nashville, TN 37212, USA. Electronic address:

It has been proposed that xanthone derivatives with anticancer potential act as topoisomerase II inhibitors because they interfere with the ability of the enzyme to bind its ATP cofactor. In order to further characterize xanthone mechanism and generate compounds with potential as anticancer drugs, we synthesized a series of derivatives in which position 3 was substituted with different polyamine chains. As determined by DNA relaxation and decatenation assays, the resulting compounds are potent topoisomerase IIα inhibitors. Although xanthone derivatives inhibit topoisomerase IIα-catalyzed ATP hydrolysis, mechanistic studies indicate that they do not act at the ATPase site. Rather, they appear to function by blocking the ability of DNA to stimulate ATP hydrolysis. On the basis of activity, competition, and modeling studies, we propose that xanthones interact with the DNA cleavage/ligation active site of topoisomerase IIα and inhibit the catalytic activity of the enzyme by interfering with the DNA strand passage step.
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http://dx.doi.org/10.1016/j.bmcl.2017.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5623067PMC
October 2017

Curcumin in Alzheimer's disease: Can we think to new strategies and perspectives for this molecule?

Pharmacol Res 2017 Oct 12;124:146-155. Epub 2017 Aug 12.

Department of Drug Sciences, University of Pavia, Italy. Electronic address:

Population aging is an irreversible global trend with economic and socio-political consequences. One of the most invalidating outcomes of aging in the elderly is cognitive decline, leading to dementia and often related to neurodegenerative disorders. Among these latter, Alzheimer's disease (AD) is the major cause of dementia, affecting more than 30 million of individuals worldwide. To date, the treatment of AD remains a challenge because of an incomplete understanding of the events that lead to the selective neurodegeneration typical of Alzheimer's brains. There is an enormous global demand for new effective therapies and researchers are investigating new fields. One promising strategy is the use of nutraceuticals as integrative, complementary and preventive therapy. Curcumin is one example of natural product with anti-AD properties, with promising potential for prevention, treatment and diagnostic. The limitations in the use of curcumin as therapeutic are represented by its pharmacokinetics profile and the low bioavailability after oral administration. However, curcumin has been the focus of intense research for new drug development. Here we analyzed some new approaches that have been applied in the attempt to improve its use, particularly new formulations, changes in the way of administration, nanotechnology-based delivery systems and the hybridization strategy.
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http://dx.doi.org/10.1016/j.phrs.2017.08.004DOI Listing
October 2017

Multitarget drug design strategy in Alzheimer's disease: focus on cholinergic transmission and amyloid-β aggregation.

Future Med Chem 2017 06 20;9(10):953-963. Epub 2017 Jun 20.

Department of Pharmacy & Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.

Aim: Alzheimer pathogenesis has been associated with a network of processes working simultaneously and synergistically. Over time, much interest has been focused on cholinergic transmission and its mutual interconnections with other active players of the disease. Besides the cholinesterase mainstay, the multifaceted interplay between nicotinic receptors and amyloid is actually considered to have a central role in neuroprotection. Thus, the multitarget drug-design strategy has emerged as a chance to face the disease network.

Methods: By exploiting the multitarget approach, hybrid compounds have been synthesized and studied in vitro and in silico toward selected targets of the cholinergic and amyloidogenic pathways.

Results: The new molecules were able to target the cholinergic system, by joining direct nicotinic receptor stimulation to acetylcholinesterase inhibition, and to inhibit amyloid-β aggregation.

Conclusion: The compounds emerged as a suitable starting point for a further optimization process.
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http://dx.doi.org/10.4155/fmc-2017-0039DOI Listing
June 2017

Quinazoline based α-adrenoreceptor antagonists with potent antiproliferative activity in human prostate cancer cell lines.

Eur J Med Chem 2017 Aug 4;136:259-269. Epub 2017 May 4.

Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy. Electronic address:

New α-adrenoreceptor (α-AR) antagonists related to prazosin and doxazosin were synthesized by replacing piperazine ring with (S)- or (R)-3-aminopiperidine. Binding studies indicated that the S configuration at the 3-C position of the piperidine ring is crucial for an optimal interaction of the compounds at all three α-AR subtypes. Quinazolines 9 and 10, bearing a quinone ring on the lateral chain, exhibited also potent antiproliferative activity in LNCaP androgen-sensitive prostate cancer cell lines, higher than that of doxazosin. Compound 10 increased apoptosis, in terms of DNA fragmentation, without triggering cell necrosis. The prooxidant activity found in compound 10 may underlie its ability to inhibit cell proliferation in synergy with the effect mediated by α-AR antagonism. Due to its better biological profile compared to doxazosin for LNCaP cell line, compound 10 might be a valuable lead compound for the design of new prostate antitumor agents.
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http://dx.doi.org/10.1016/j.ejmech.2017.05.003DOI Listing
August 2017

Targeting the Nrf2/Amyloid-Beta Liaison in Alzheimer's Disease: A Rational Approach.

ACS Chem Neurosci 2017 07 25;8(7):1618-1627. Epub 2017 Apr 25.

Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna , Via Belmeloro 6, 40126 Bologna, Italy.

Amyloid is a prominent feature of Alzheimer's disease (AD). Yet, a linear linkage between amyloid-β peptide (Aβ) and the disease onset and progression has recently been questioned. In this context, the crucial partnership between Aβ and Nrf2 pathways is acquiring paramount importance, offering prospects for deciphering the Aβ-centered disease network. Here, we report on a new class of antiaggregating agents rationally designed to simultaneously activate transcription-based antioxidant responses, whose lead 1 showed interesting properties in a preliminary investigation. Relying on the requirements of Aβ recognition, we identified the catechol derivative 12. In SH-SY5Y neuroblastoma cells, 12 combined remarkable free radical scavenger properties to the ability to trigger the Nrf2 pathway and induce the Nrf2-dependent defensive gene NQO1 by means of electrophilic activation of the transcriptional response. Moreover, 12 prevented the formation of cytotoxic stable oligomeric intermediates, being significantly more effective, and per se less toxic, than prototype 1. More importantly, as different chemical features were exploited to regulate Nrf2 and Aβ activities, the two pathways could be tuned independently. These findings point to compound 12 and its derivatives as promising tools for investigating the therapeutic potential of the Nrf2/Aβ cellular network, laying foundation for generating new drug leads to confront AD.
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http://dx.doi.org/10.1021/acschemneuro.7b00100DOI Listing
July 2017

Polyamine Conjugation as a Promising Strategy To Target Amyloid Aggregation in the Framework of Alzheimer's Disease.

ACS Med Chem Lett 2016 Dec 26;7(12):1145-1150. Epub 2016 Sep 26.

Department of Pharmacy & Biotechnology, Alma Mater Studiorum-University of Bologna , Via Belmeloro 6, 40126 Bologna, Italy.

Spermine conjugates -, carrying variously decorated 3,5-dibenzylidenepiperidin-4-one as bioactive motives, were designed to direct antiaggregating properties into mitochondria, using a polyamine functionality as the vehicle tool. The study confirmed mitochondrial import of the catechol derivative , which displayed effective antiaggregating activity and neuroprotective effects against Aβ-induced toxicity. Notably, a key functional role for the polyamine motif in Aβ molecular recognition was also unraveled. This experimental readout, which was supported by in silico studies, gives important new insight into the polyamine's action. Hence, we propose polyamine conjugation as a promising strategy for the development of neuroprotectant leads that may contribute to decipher the complex picture of Aβ toxicity.
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http://dx.doi.org/10.1021/acsmedchemlett.6b00339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5150688PMC
December 2016

In Vivo Characterization of ARN14140, a Memantine/Galantamine-Based Multi-Target Compound for Alzheimer's Disease.

Sci Rep 2016 09 9;6:33172. Epub 2016 Sep 9.

Drug Discovery and Development, Istituto Italiano di Tecnologia, Genova, Italy.

Alzheimer's disease (AD) is a chronic pathological condition that leads to neurodegeneration, loss of intellectual abilities, including cognition and memory, and ultimately to death. It is widely recognized that AD is a multifactorial disease, where different pathological cascades (mainly amyloid and tau) contribute to neural death and to the clinical outcome related to the disease. The currently available drugs for AD were developed according to the one-target, one-drug paradigm. In recent times, multi-target strategies have begun to play an increasingly central role in the discovery of more efficacious candidates for complex neurological conditions, including AD. In this study, we report on the in vivo pharmacological characterization of ARN14140, a new chemical entity, which was obtained through a multi-target structure-activity relationship campaign, and which showed a balanced inhibiting profile against the acetylcholinesterase enzyme and the NMDA receptor. Based on the initial promising biochemical data, ARN14140 is here studied in mice treated with the amyloidogenic fragment 25-35 of the amyloid-β peptide, a consolidated non-transgenic AD model. Sub-chronically treating animals with ARN14140 leads to a prevention of the cognitive impairment and of biomarker levels connected to neurodegeneration, demonstrating its neuroprotective potential as new AD agent.
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http://dx.doi.org/10.1038/srep33172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5016838PMC
September 2016

Multitarget strategies in Alzheimer's disease: benefits and challenges on the road to therapeutics.

Future Med Chem 2016 04 15;8(6):697-711. Epub 2016 Apr 15.

Department of Pharmacy & Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.

Alzheimer's disease is a multifactorial syndrome, for which effective cures are urgently needed. Seeking for enhanced therapeutic efficacy, multitarget drugs have been increasingly sought after over the last decades. They offer the attractive prospect of tackling intricate network effects, but with the benefits of a single-molecule therapy. Herein, we highlight relevant progress in the field, focusing on acetylcholinesterase inhibition and amyloid pathways as two pivotal features in multitarget design strategies. We also discuss the intertwined relationship between selected molecular targets and give a brief glimpse into the power of multitarget agents as pharmacological probes of Alzheimer's disease molecular mechanisms.
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http://dx.doi.org/10.4155/fmc-2016-0003DOI Listing
April 2016

Nature-Inspired Multifunctional Ligands: Focusing on Amyloid-Based Molecular Mechanisms of Alzheimer's Disease.

ChemMedChem 2016 06 26;11(12):1309-17. Epub 2015 Oct 26.

Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy.

The amyloidogenic pathway is a prominent feature of Alzheimer's disease (AD). However, growing evidence suggests that a linear disease model based on β-amyloid peptide (Aβ) alone is not likely to be realistic, which therefore calls for further investigations on the other actors involved in the play. The pro-oxidant environment induced by Aβ in AD pathology is well established, and a correlation among Aβ, oxidative stress, and conformational changes in p53 has been suggested. In this study, we applied a multifunctional approach to identify allyl thioesters of variously substituted trans-cinnamic acids for which the pharmacological profile was strategically tuned by hydroxy substituents on the aromatic moiety. Indeed, only catechol derivative 3 [(S)-allyl (E)-3-(3,4-dihydroxyphenyl)prop-2-enethioate] inhibited Aβ fibrilization. Conversely, albeit to different extents, all compounds were able to decrease the formation of reactive oxygen species in SH-SY5Y neuroblastoma cells and to prevent alterations in the conformation of p53 and its activity mediated by soluble sub-lethal concentrations of Aβ. This may support an involvement of oxidative stress in Aβ function, with p53 emerging as a potential mediator of their functional interplay.
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http://dx.doi.org/10.1002/cmdc.201500422DOI Listing
June 2016

An optimized polyamine moiety boosts the potency of human type II topoisomerase poisons as quantified by comparative analysis centered on the clinical candidate F14512.

Chem Commun (Camb) 2015 Oct 3;51(76):14310-3. Epub 2015 Aug 3.

Laboratory of Molecular Modeling and Drug Discovery, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.

Combined computational-experimental analyses explain and quantify the spermine-vectorized F14512's boosted potency as a topoII poison. We found that an optimized polyamine moiety boosts drug binding to the topoII/DNA cleavage complex, rather than to the DNA alone. These results provide new structural bases and key reference data for designing new human topoII poisons.
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http://dx.doi.org/10.1039/c5cc05065kDOI Listing
October 2015

Polypharmacology: the rise of multitarget drugs over combination therapies.

Authors:
Michela Rosini

Future Med Chem 2014 Apr;6(5):485-7

Department of Pharmacy & Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.

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http://dx.doi.org/10.4155/fmc.14.25DOI Listing
April 2014

Multi-target design strategies in the context of Alzheimer's disease: acetylcholinesterase inhibition and NMDA receptor antagonism as the driving forces.

Neurochem Res 2014 Oct 4;39(10):1914-23. Epub 2014 Feb 4.

Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy,

In recent years, the multi-target-directed ligand concept has been used to design a variety of molecules hitting different biological targets for Alzheimer's disease. We have sought to combine, in the same molecule, the neuroprotective action of N-methyl-D-aspartate receptor antagonism with the symptomatic relief offered by cholinergic activity through acetylcholinesterase inhibition. This strategy could potentially maintain the positive outcomes of memantine-acetylcholinesterase inhibitor combinations, but with the benefits of a single molecule therapy. Herein, we discuss selected examples of multifunctional compounds, which we rationally designed to simultaneously modulate these targets. We also examine the intertwined relationship between acetylcholinesterase, N-methyl-D-aspartate receptors, and other active players in the neurotoxic cascade.
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http://dx.doi.org/10.1007/s11064-014-1250-1DOI Listing
October 2014

Oxidative stress in Alzheimer's disease: are we connecting the dots?

J Med Chem 2014 Apr 5;57(7):2821-31. Epub 2013 Nov 5.

Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna , Via Belmeloro 6, 40126 Bologna, Italy.

Redox impairment is a prominent feature of Alzheimer's disease (AD). It has led to the "oxidative stress hypothesis", which proposes antioxidants as beneficial therapeutic tools in AD treatment. To date, a wide variety of antioxidants have been examined as neuroprotectants. However, success has been elusive in clinical trials. Several factors have contributed to this failure, including the complexity of the redox system in vivo. Potentially critical aspects include the fine-tuned equilibrium between antioxidant defenses and free radical production, the lack of specific antioxidant target(s), and the inherent difficulty in delivering antioxidants where they are needed. Herein, we highlight significant progress in the field. Future directions of antioxidant research are also presented.
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http://dx.doi.org/10.1021/jm400970mDOI Listing
April 2014

Multifunctional tacrine derivatives in Alzheimer's disease.

Curr Top Med Chem 2013 ;13(15):1771-86

Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.

Tacrine (1) was the first acetylcholinesterase inhibitor (AChEI) introduced in therapy for the treatment of Alzheimer's disease (AD), but similarly to the most recent approved AChEIs and memantine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, it does not represent an effective drug in halting the progression of AD. The continuous research in this field has contributed to delineate AD as a multifactorial syndrome with several biological targets involved in its etiology. On these bases, the development of new effective therapeutics becomes crucial and the design of molecules that address more than one specific AD target should represent thus a succeeded strategy for AD treatment. This review will focus on and summarize multifunctional 1 derivatives starting from our last paper published on the same topic in 2010. In the last three years, the design and synthesis of 1 homo- and heterodimers, as well as of 1-hybrid structures for AD therapy, was aimed mainly to discover safer drugs, with decreased hepatotoxicity in comparison to 1, taking also into account the multifactorial pathogenesis of the disease. Most of these new hetero/homo-dimers and/or hybrids of 1, although addressed mainly to acetylcholinesterase (AChE) and Aβ aggregation inhibition, are able to hit additional targets relevant to AD, among which, β-secretase (BACE1), reactive oxygen species (ROS), calcium channels, NMDAR and M1- muscarinic receptors.
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http://dx.doi.org/10.2174/15680266113139990136DOI Listing
March 2014

Exploiting RNA as a new biomolecular target for synthetic polyamines.

Gene 2013 Jul 19;524(2):232-40. Epub 2013 Apr 19.

Department of Pharmacy and BioTechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.

Anticancer chemotherapy is strongly hampered by the low therapeutic index of most anticancer drugs and the development of chemoresistance. Therefore, there is a continued need for the identification of new molecular targets in order to selectively hit cancer cells. RNA has been recently validated as a cancer target by the use of different specific ligands and/or by different agents able to destroy its diverse forms. The ability of synthetic polyamines to interact and to alter the RNA structure has been already reported. In the present paper the interaction and the ability to damage RNA structure by several synthetic polyamines were evaluated and quantified by microfluid capillary electrophoresis. This technique allowed us to visualize both the RNA impairment through different electropherograms and to assess the RNA integrity number. Finally, the ability to discriminate between RNA and DNA by these synthetic polyamines was also evaluated.
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http://dx.doi.org/10.1016/j.gene.2013.04.016DOI Listing
July 2013

Combining galantamine and memantine in multitargeted, new chemical entities potentially useful in Alzheimer's disease.

J Med Chem 2012 Nov 17;55(22):9708-21. Epub 2012 Oct 17.

Drug Discovery and Development, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.

Herein we report on a novel series of multitargeted compounds obtained by linking together galantamine and memantine. The compounds were designed by taking advantage of the crystal structures of acetylcholinesterase (AChE) in complex with galantamine derivatives. Sixteen novel derivatives were synthesized, using spacers of different lengths and chemical composition. The molecules were then tested as inhibitors of AChE and as binders of the N-methyl-d-aspartate (NMDA) receptor (NMDAR). Some of the new compounds were nanomolar inhibitors of AChE and showed micromolar affinities for NMDAR. All compounds were also tested for selectivity toward NMDAR containing the 2B subunit (NR2B). Some of the new derivatives showed a micromolar affinity for NR2B. Finally, selected compounds were tested using a cell-based assay to measure their neuroprotective activity. Three of them showed a remarkable neuroprotective profile, inhibiting the NMDA-induced neurotoxicity at subnanomolar concentrations (e.g., 5, named memagal, IC(50) = 0.28 nM).
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http://dx.doi.org/10.1021/jm3009458DOI Listing
November 2012

Structure-activity relationships of novel substituted naphthalene diimides as anticancer agents.

Eur J Med Chem 2012 Nov 4;57:417-28. Epub 2012 Jul 4.

Dipartimento di Scienze Farmaceutiche, Alma Mater Studiorum, University di Bologna, Via Belmeloro 6, 40126 Bologna, Italy.

Novel 1,4,5,8-naphthalenetetracarboxylic diimide (NDI) derivatives were synthesized and evaluated for their antiproliferative activity on a wide number of different tumor cell lines. The prototypes of the present series were derivatives 1 and 2 characterized by interesting biological profiles as anticancer agents. The present investigation expands on the study of structure-activity relationships of prototypes 1 and 2, namely, the influence of the different substituents of the phenyl rings on the biological activity. Derivatives 3-22, characterized by a different substituent on the aromatic rings and/or a different chain length varying from two to three carbon units, were synthesized and evaluated for their cytostatic and cytotoxic activities. The most interesting compound was 20, characterized by a linker of three methylene units and a 2,3,4-trimethoxy substituent on the two aromatic rings. It displayed antiproliferative activity in the submicromolar range, especially against some different cell lines, the ability to inhibit Taq polymerase and telomerase, to trigger caspase activation by a possible oxidative mechanism, to downregulate ERK 2 protein and to inhibit ERKs phosphorylation, without acting directly on microtubules and tubuline. Its theoretical recognition against duplex and quadruplex DNA structures have been compared to experimental thermodynamic measurements and by molecular modeling investigation leading to putative binding modes. Taken together these findings contribute to define this compound as potential Multitarget-Directed Ligands interacting simultaneously with different biological targets.
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http://dx.doi.org/10.1016/j.ejmech.2012.06.045DOI Listing
November 2012