522 results on '"Andrisano, V."'
Search Results
102. Acetylcholinesterase Noncovalent Inhibitors Based on a Polyamine Backbone for Potential Use against Alzheimer's Disease
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Melchiorre, C., Andrisano, V., Bolognesi, M. L., Budriesi, R., Cavalli, A., Cavrini, V., Rosini, M., Tumiatti, V., and Recanatini, M.
- Published
- 1998
103. Acetylcholinesterase Inhibitors: Synthesis and Structure−Activity Relationships of ω-[N-Methyl-N-(3-alkylcarbamoyloxyphenyl)- methyl]aminoalkoxyheteroaryl Derivatives
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Rampa, A., Bisi, A., Valenti, P., Recanatini, M., Cavalli, A., Andrisano, V., Cavrini, V., Fin, L., Buriani, A., and Giusti, P.
- Abstract
Acetylcholinesterase (AChE) inhibitors are one of the most actively investigated classes of compounds in the search for an effective treatment of Alzheimer's disease. This work describes the synthesis, AChE inhibitory activity, and structure−activity relationships of some compounds related to a recently discovered series of AChE inhibitors: the ω-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyxanthen-9-ones. The influence of structural variations on the inhibitory potency was carefully investigated by modifying different parts of the parent molecule, and a theoretical model of the binding of one representative compound to the enzyme was developed. The biological properties of the series were investigated in some detail by considering not only the activity on isolated enzyme but the selectivity with respect to butyrylcholinesterase (BuChE) and the in vitro inhibitory activity on rat cerebral cortex as well. Some of the newly synthesized derivatives, when tested on isolated and/or AChE-enriched rat brain cortex fraction, displayed a selective inhibitory activity and were more active than physostigmine. In particular, compound
13 , an azaxanthone derivative, displayed the best rat cortex AChE inhibition (190-fold higher than physostigmine), as well as a high degree of enzyme selectivity (over 60-fold more selective for AChE than for BuChE). When tested in the isolated enzyme, compound13 was less active, suggesting some differences either in drug availability/biotransformation or in the inhibitor-sensitive residues of the enzyme when biologically positioned in rat brain membranes.- Published
- 1998
104. HPLC Determination of Chloramphenicol and Thiamphenicol Residues in Gamebird Meats
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Pietra, A. M. Di, Piazza, V., Andrisano, V., and Cavrini, V.
- Abstract
Liquid chromatographic methods for the determination of chloramphenicol (CAP) and thiamphenicol (TAP) residues in gamebird (pheasant, mallard and quail) meats were developed. The drugs were extracted from the homogenised tissues (muscle and liver) by water and the extracts were purified by subsequent partitions with Chem Elut CE 1020 cartridge - ethyl acetate and water - toluene. The recoveries were 67% for CAP and 72% for TAP. Chromatographic separations were performed on a Hypersil C-18 column and the peak identification and quantitation was made with a photodiode array detector. Using the first derivative of the chromatographic peak the selectivity of the analysis was improved. The elimination kinetics of CAP and TAP from the quail tissues were also evaluated.
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- 1995
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105. Acetylcholinesterase inhibition by tacrine analogues
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Valenti, P., Rampa, A., Bisi, A., Andrisano, V., Cavrini, V., Fin, L., Burianil, A., and Giusti, P.
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- 1997
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106. On-line post-column photochemical derivatization in liquid chromatographic-diode-array detection analysis of binary drug mixtures
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Pietra, A. M. Di, Andrisano, V., Gotti, R., and Cavrini, V.
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- 1996
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107. Analytical study of penicillamine in pharmaceuticals by capillary zone electrophoresis
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Gotti, R., Pomponio, R., Andrisano, V., and Cavrini, V.
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- 1999
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108. Two-carbon bridge substituted cocaines: enantioselective synthesis, attribution of the absolute configuration and biological activity of novel 6- and 7-methoxylated cocaines
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Simoni, D., Roberti, M., Andrisano, V., Manferdini, M., Rondanin, R., and Invidiata, F.P.
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- 1999
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109. Comparative evaluation of three chromatographic methods in the quality control of fatty alcohols for pharmaceutical and cosmetic use
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Andrisano, V., roberto gotti, Di Pietra, A. M., and Cavrini, V.
110. Bioflavonoids - A new oligomeric derivative of rutin in the treatment of facial telangiectases
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Manuzzi, P., antonella tosti, Andrisano, V., Scapini, G., and Tumiatti, V.
111. Derivative UV spectrophotometric determination of atenolol and metoprolol in single- and multi-component pharmaceutical dosage forms
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Bonazzi, D., roberto gotti, Andrisano, V., and Cavrini, V.
112. Capillary electrophoretic and high-performance liquid chromatographic studies of the enantioselective separation of α 1-adrenoreceptor antagonists
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Andrisano, V, Gotti, R, Cavrini, V, Tumiatti, V, Felix, G, and Wainer, I.W
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- 1998
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113. Sparteine as mobile phase modifier in the chiral separation of hydrophobic basic drugs on an α 1-acid glycoprotein column
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Makamba, H, Andrisano, V, Gotti, R, Cavrini, V, and Felix, G
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- 1998
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114. ChemInform Abstract: Unusual Reaction of 1,4-Diamino-2-nitrobenzene Derivatives Toward Nucleophiles: Catalysis by Sodium Sulfite.
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FORLANI, L., BOGA, C., MAZZA, M., CAVRINI, V., and ANDRISANO, V.
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- 1998
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115. ChemInform Abstract: Cholinergic Agents. Synthesis and Acetylcholinesterase Inhibitory Activity of Some ω-(N-Methyl-N-(3-alkylcarbamoyloxyphenyl)- methyl)aminoalkoxyxanthen-9-ones.
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VALENTI, P., RAMPA, A., BISI, A., FABBRI, G., ANDRISANO, V., and CAVRINI, V.
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- 1995
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116. HPLC determination of glutathione and L-cysteine in pharmaceuticals after derivatization with ethacrynic acid
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Pietra, A. M. Di, Gotti, R., Bonazzi, D., and Andrisano, V.
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- 1994
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117. Multifunctional Cholinesterase and Amyloid Beta Fibrillization Modulators. Synthesis and Biological Investigation
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Egeria Guarino, Ersilia De Lorenzi, Simone Brogi, Ved Chauhan, Stefania Butini, Laura Verga, Ashima Saxena, Samuele Maramai, Ettore Novellino, Raffaella Colombo, Margherita Brindisi, Manuela Bartolini, Alessandro Panico, Vincenza Andrisano, Giuseppe Campiani, Sandra Gemma, Butini S, Brindisi M, Brogi S, Maramai S, Guarino E, Panico A, Saxena A, Chauhan V, Colombo R, Verga L, De Lorenzi E, Bartolini M, Andrisano V, Novellino E, Campiani G, Gemma S, Butini, S., Brindisi, M, Brogi, S., Maramai, S., Guarino, E., Panico, A, Saxena, A, Chauhan, V., Colombo, R, Verga, L., De Lorenzi, E., Bartolini, M., Andrisano, V, Novellino, Ettore, Campiani, G., and Gemma, S.
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amyloid beta-peptides ,Amyloid beta ,Peptide ,Biochemistry ,Cholinesterase inhibitors ,multifunctional tools ,chemistry.chemical_compound ,Alzheimer's disease ,amyloid beta oligomers ,bivalent ligands ,Drug Discovery ,Moiety ,Cholinesterase ,chemistry.chemical_classification ,biology ,Organic Chemistry ,Combinatorial chemistry ,Acetylcholinesterase ,Enzyme ,chemistry ,biology.protein ,Biophysics - Abstract
In order to identify novel Alzheimer's modifying pharmacological tools, we developed bis-tacrines bearing a peptide moiety for specific interference with surface sites of human acetylcholinesterase (hAChE) binding amyloid-beta (A beta). Accordingly, compounds 2a-c proved to be inhibitors of hAChE catalytic and noncatalytic functions, binding the catalytic and peripheral sites, interfering with A beta aggregation and with the A beta self-oligomerization process (2a). Compounds 2a-c in complex with TcAChE span the gorge with the bis-tacrine system, and the peptide moieties bulge outside the gorge in proximity of the peripheral site These moieties are likely responsible for the observed reduction of hAChE-induced A beta aggregation since they physically hamper A beta binding to the enzyme surface. Moreover, 2a was able to significantly interfere with A beta self-oligornerization, while 2b,c showed improved inhibition of hAChE-induced A beta aggregation.
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- 2013
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118. Protein Flexibility in Virtual Screening: The BACE-1 Case Study
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Vincenza Andrisano, Valeria La Pietra, David S. Goodsell, Angela De Simone, Sandro Cosconati, Luciana Marinelli, Francesca Mancini, Arthur J. Olson, Ettore Novellino, Francesco Saverio Di Leva, S., Cosconati, Marinelli, Luciana, Di Leva, Francesco Saverio, LA PIETRA, Valeria, A., De Simone, F., Mancini, V., Andrisano, Novellino, Ettore, D. S., Goodsell, A. J., Olson, Cosconati S., Marinelli L., Di Leva F.S., La Pietra V., De Simone A., Mancini F., Andrisano V., Novellino E., Goodsell D.S., Olson A.J., Cosconati, Sandro, Marinelli, L, Di Leva, F, La Pietra, V, De Simone, A, Mancini, F, Andrisano, V, Novellino, E, Goodsell, D, and Olson, A. J.
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STRUCTURE-BASED DESIGN ,FLEXIBLE SIDE-CHAINS ,MEMAPSIN-2 BETA-SECRETASE ,APP CLEAVING ENZYME ,DRUG DESIGN ,MOLECULAR RECOGNITION ,ALZHEIMERS-DISEASE ,LIGAND DOCKING ,SOFT DOCKING ,ACTIVE-SITE ,Protein Conformation ,General Chemical Engineering ,Library and Information Sciences ,Machine learning ,computer.software_genre ,Crystallography, X-Ray ,Ligands ,Molecular Docking Simulation ,Article ,Antiparkinson Agents ,User-Computer Interface ,Alzheimer Disease ,High-Throughput Screening Assays ,Drug Discovery ,Fluorescence Resonance Energy Transfer ,Aspartic Acid Endopeptidases ,Humans ,Simulation ,Virtual screening ,Binding Sites ,Chemistry ,business.industry ,Drug discovery ,General Chemistry ,Grid ,Computer Science Applications ,Weighting ,Thermodynamics ,Artificial intelligence ,Amyloid Precursor Protein Secretases ,business ,computer ,Algorithms ,Databases, Chemical ,Protein Binding - Abstract
Simulating protein flexibility is a major issue in the docking-based drug-design process for which a single methodological solution does not exist. In our search of new anti-Alzheimer ligands, we were faced with the challenge of including receptor plasticity in a virtual screening campaign aimed at finding new β-secretase inhibitors. To this aim, we incorporated protein flexibility in our simulations by using an ensemble of static X-ray enzyme structures to screen the National Cancer Institute database. A unified description of the protein motion was also generated by computing and combining a set of grid maps using an energy weighting scheme. Such a description was used in an energy-weighted virtual screening experiment on the same molecular database. Assessment of the enrichment factors from these two virtual screening approaches demonstrated comparable predictive powers, with the energy-weighted method being faster than the ensemble method. The in vitro evaluation demonstrated that out of the 32 tested ligands, 17 featured the predicted enzyme inhibiting property. Such an impressive success rate (53.1%) demonstrates the enhanced power of the two methodologies and suggests that energy-weighted virtual screening is a more than valid alternative to ensemble virtual screening given its reduced computational demands and comparable performance. © 2012 American Chemical Society.
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- 2012
119. Novel class of quinone-bearing polyamines as multi-target-directed ligands to combat Alzheimer's disease
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Andrea Cavalli, Anna Minarini, Antonino Cattaneo, Michela Rosini, Andrea Tarozzi, Vincenza Andrisano, Maria Laura Bolognesi, Patrizia Hrelia, Giorgio Lenaz, Rita Banzi, Manuela Bartolini, Christian Bergamini, Carlo Melchiorre, Romana Fato, Vincenzo Tumiatti, Maurizio Recanatini, Bolognesi ML, Banzi R, Bartolini M, Cavalli A, Tarozzi A, Andrisano V, Minarini A, Rosini M, Tumiatti V, Bergamini C, Fato R, Lenaz G, Hrelia P, Cattaneo A, Recanatini M, Melchiorre C., Bolognesi, Ml, Banzi, R, Bartolini, M, Cavalli, A, Tarozzi, A, Andrisano, V, Minarini, A, Rosini, M, Tumiatti, V, Bergamini, C, Fato, R, Lenaz, G, Hrelia, P, Cattaneo, Antonino, Recanatini, M, and Melchiorre, C.
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Models, Molecular ,Amyloid beta ,Plasma protein binding ,medicine.disease_cause ,Ligands ,Antioxidants ,MULTITARGET ,Cell Line ,Substrate Specificity ,chemistry.chemical_compound ,Structure-Activity Relationship ,Alzheimer Disease ,Drug Discovery ,medicine ,NAD(P)H Dehydrogenase (Quinone) ,Polyamines ,Structure–activity relationship ,Humans ,Binding site ,Butyrylcholinesterase ,Amyloid beta-Peptides ,Binding Sites ,biology ,Chemistry ,Quinones ,medicine.disease ,AMYLOID-BETA ,Acetylcholinesterase ,Oxidative Stress ,Biochemistry ,ALZHEIMER'S DISEASE ,biology.protein ,Molecular Medicine ,Cholinesterase Inhibitors ,Alzheimer's disease ,Reactive Oxygen Species ,Oxidative stress ,Protein Binding - Abstract
One of the characteristics of Alzheimer's disease (AD) that hinders the discovery of effective disease-modifying therapies is the multifactorial nature of its etiopathology. To circumvent this drawback, the use of multi-target-directed ligands (MTDLs) has recently been proposed as a means of simultaneously hitting several targets involved in the development of the AD syndrome. In this paper, a new class of MTDLs based on a polyamine-quinone skeleton, whose lead (memoquin, 2) showed promising properties in preclinical investigations (Cavalli et al. Angew. Chem., Int. Ed. 2007, 46, 3689-3692), is described. 3-29 were tested in vitro against a number of isolated AD-related targets, namely, AChE and BChE, and Abeta aggregation (both AChE-mediated and self-induced). Furthermore, the ability of the compounds to counteract the oxidative stress in a human neuronal-like cellular system (SH-SY5Y cells) was assayed, in both the presence and absence of NQO1, an enzyme able to generate and maintain the reduced form of quinone.
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- 2007
120. A small molecule targeting the multifactorial nature of Alzheimer's disease
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Manuela Bartolini, Maria Laura Bolognesi, Simona Capsoni, Vincenza Andrisano, Carlo Melchiorre, Elisa Margotti, Antonino Cattaneo, Andrea Cavalli, Maurizio Recanatini, Cavalli, A, Bolognesi, Ml, Capsoni, Simona, Andrisano, V, Bartolini, M, Margotti, E, Cattaneo, Antonino, Recanatini, M, Melchiorre, C., Cavalli A., Bolognesi M. L., Capsoni S., Andrisano V., Bartolini M., Margotti E., Cattaneo A., Recanatini M., and Melchiorre C.
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Models, Molecular ,Amyloid β ,Drug Evaluation, Preclinical ,Socio-culturale ,Mice, Transgenic ,Disease ,Pharmacology ,Catalysis ,Lesion ,Mice ,Structure-Activity Relationship ,Drug Delivery Systems ,Alzheimer Disease ,Alkanes ,Ethylamines ,medicine ,Animals ,Humans ,Molecular Structure ,Chemistry ,Neurodegeneration ,Stereoisomerism ,General Medicine ,General Chemistry ,medicine.disease ,Small molecule ,Mice transgenic ,Disease Models, Animal ,Tau phosphorylation ,medicine.symptom ,Alzheimer's disease ,Neuroscience - Abstract
Alzheimer s disease (AD) is a complex multifactorial syndrome unlikely to arise from a single causal factor, but due to a number of different but related biological alterations that contribute to its pathogenesis. None of the presently marketed drugs, although valuable in improving cognitive, behavioral, and functional impairments, alter AD progression, and the goal of an effective disease-modifying treatment is still unmet. Nowadays, mechanism-based drug-design approaches are mainly directed toward two proteins, amyloid b (Ab) and tau. Ab is the core constituent of senile plaques, one of the key pathological characteristics of AD, whereas phosphorylated tau is the main component of neurofibrillary tangles, the other hallmark lesion of AD. Despite enormous research effort, no new molecules that interfere with the biochemical pathways of either Ab or tau have been approved so far for the treatment of AD. This failure is probably due to the weakness of the classic drug discovery approach based on the “one molecule, one target” paradigm, which might prove inadequate when the molecular complexity of the disease is addressed. In fact, the multifactorial nature of AD and the current lack of an accepted unitary theory to account for AD neurodegeneration have formed the basis of a growing consensus that single compounds are required that are able to interact with several molecular targets in the neurotoxic cascade (the innovative “one molecule, multiple targets” paradigm). Herein, we report on a new drug candidate (memoquin, patent pending) derived from a program aimed at creating multifunctional molecules to interfere with different key target points of AD neurodegeneration.
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- 2007
121. Memoquin: a new therapeutic poly-agent for Alzheimer's disease
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ANDREA CAVALLI, Maria Laura Bolognesi, Manuela Bartolini, VINCENZA ANDRISANO, Melchiorre, Carlo, Maurizio Recanatini, Margotti, E., Capsoni, S., Cattaneo, A., Cavalli A., Bolognesi M.L., Bartolini M., Andrisano V., Melchiorre C., Recanatini M., Margotti E., Capsoni S., Cattaneo A., Cavalli, A, Bolognesi, Ml, Bartolini, M, Andrisano, V, Melchiorre, C, Recanatini, M, Margotti, E, Capsoni, Simona, and Cattaneo, Antonino
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Socio-culturale - Abstract
In this study, we present a new molecule, Memoquin, designed to display a range of activities potentially beneficial at distinct levels of the AD neuropathology. In vitro, this compound is able not only to inhibit acetylcholinesterase (AChE) activity, but it is also able to block in vitro the Abeta aggregation induced by AChE and shows anti-oxidant activity. In vivo, Memoquin was able to rescue, at the behavioral level, cognitive deficits in mice in which amnesia was induced by scopolamine and in AD11 anti-NGF transgenic mice. From the neuropathological point of view, in this comprehensive model for sporadic AD-like neurodegeneration, the oral admistration of Memoquin causes an effective recovery from the observed cholinergic deficit, tau hyperphosphorylation, beta-amyloid deposition. These findings show that a multiple therapeutic approach can be realized through properly designed molecules.
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- 2004
122. Pyridinylimidazoles as GSK3β Inhibitors: The Impact of Tautomerism on Compound Activity via Water Networks
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Mark Kudolo, Stefan Laufer, Francesco Ansideri, Taiane Schneider, Fabian Heider, Letizia Pruccoli, Pierre Koch, Andrea Tarozzi, Angela De Simone, Márcia Inês Goettert, Vincenza Andrisano, Tatu Pantsar, Heider F., Pantsar T., Kudolo M., Ansideri F., De Simone A., Pruccoli L., Schneider T., Goettert M.I., Tarozzi A., Andrisano V., Laufer S.A., and Koch P.
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Stereochemistry ,Drug target ,Protein kinase inhibitors ,quantum mechanic ,glycogen synthase kinase-3β ,molecular dynamics simulation ,pyridinylimidazoles ,quantum mechanics ,tautomerism ,01 natural sciences ,Biochemistry ,Drug Discovery ,Ic50 values ,Protein kinase A ,Glycogen synthase ,biology ,010405 organic chemistry ,Kinase ,Chemistry ,Organic Chemistry ,Dual inhibitor ,Tautomer ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,pyridinylimidazole ,Protein kinase inhibitor ,biology.protein ,Selectivity - Abstract
[Image: see text] Glycogen synthase kinase-3β (GSK3β) is involved in many pathological conditions and represents an attractive drug target. We previously reported dual GSK3β/p38α mitogen-activated protein kinase inhibitors and identified N-(4-(4-(4-fluorophenyl)-2-methyl-1H-imidazol-5-yl)pyridin-2-yl)cyclopropanecarboxamide (1) as a potent dual inhibitor of both target kinases. In this study, we aimed to design selective GSK3β inhibitors based on our pyridinylimidazole scaffold. Our efforts resulted in several novel and potent GSK3β inhibitors with IC(50) values in the low nanomolar range. 5-(2-(Cyclopropanecarboxamido)pyridin-4-yl)-4-cyclopropyl-1H-imidazole-2-carboxamide (6g) displayed very good kinase selectivity as well as metabolical stability and inhibited GSK3β activity in neuronal SH-SY5Y cells. Interestingly, we observed the importance of the 2-methylimidazole’s tautomeric state for the compound activity. Finally, we reveal how this crucial tautomerism effect is surmounted by imidazole-2-carboxamides, which are able to stabilize the binding via enhanced water network interactions, regardless of their tautomeric state.
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- 2019
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123. Investigating in Vitro Amyloid Peptide 1–42 Aggregation: Impact of Higher Molecular Weight Stable Adducts
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Vincenza Andrisano, Lara Davani, Mark L. Dallas, Manuela Bartolini, Daniele Tedesco, Andrea Milelli, Angela De Simone, Marina Naldi, Darius Widera, De Simone A., Naldi M., Tedesco D., Milelli A., Bartolini M., Davani L., Widera D., Dallas M.L., and Andrisano V.
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chemistry.chemical_classification ,Circular dichroism ,drug discovery, CORM, amyloid beta, Alzheimer's disease, mass spectrometry, circular dichroism, fluorescence ,biology ,Amyloid ,Drug discovery ,Amyloid beta ,General Chemical Engineering ,Peptide ,General Chemistry ,Fibril ,Article ,In vitro ,Adduct ,lcsh:Chemistry ,lcsh:QD1-999 ,chemistry ,Biochemistry ,biology.protein - Abstract
The self-assembly of amyloid peptides (A beta), in particular A beta(1-42), into oligomers and fibrils is one of the main pathological events related to Alzheimer's disease. Recent studies have demonstrated the ability of carbon monoxide-releasing molecules (CORMs) to protect neurons and astrocytes from A beta(1-42) toxicity. In fact, CORMs are able to carry and release controlled levels of CO and are known to exert a wide range of anti-inflammatory and anti-apoptotic activities at physiologically relevant concentrations. In order to investigate the direct effects of CORMs on A beta(1-42), we studied the reactivity of CORM-2 and CORM-3 with A beta(1-42) in vitro and the potential inhibition of its aggregation by mass spectrometry (MS), as well as fluorescence and circular dichroism spectroscopies. The application of an electrospray ionization-MS (ESI-MS) method allowed the detection of stable A beta(1-42)/CORMs adducts, involving the addition of the Ru(CO)(2) portion of CORMs at histidine residues on the A beta(1-42) skeleton. Moreover, CORMs showed anti-aggregating properties through formation of stable adducts with A beta(1-42) as demonstrated by a thioflavin T fluorescence assay and MS analysis. As further proof, comparison of the CD spectra of A beta(1-42) recorded in the absence and in the presence of CORM-3 at a 1: 1 molar ratio showed the ability of CORM-3 to stabilize the peptide in its soluble, unordered conformation, thereby preventing its misfolding and aggregation. This multi-methodological investigation revealed novel interactions between A beta(1-42) and CORMs, contributing new insights into the proposed neuroprotective mechanisms mediated by CORMs and disclosing a new strategy to divert amyloid aggregation and toxicity.
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- 2019
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124. Discovery of the First-in-Class GSK-3β/HDAC Dual Inhibitor as Disease-Modifying Agent To Combat Alzheimer’s Disease
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Deborah Pietrobono, Nicola Petragnani, Vincenza Andrisano, Claudia Martini, Vincenzo Tumiatti, Nibal Betari, Serena Montanari, Simona Daniele, Lara Davani, Angela Nebbioso, Ettore Novellino, F. Frabetti, Barbara Monti, Pasquale Russomanno, Angela De Simone, Andrea Milelli, Federica Sarno, Lucia Altucci, Patrizia Ballerini, Raffaella Casadei, Valeria La Pietra, Mariarosaria Conte, Sabrina Petralla, De Simone, Angela, La Pietra, Valeria, Betari, Nibal, Petragnani, Nicola, Conte, Mariarosaria, Daniele, Simona, Pietrobono, Deborah, Martini, Claudia, Petralla, Sabrina, Casadei, Raffaella, Davani, Lara, Frabetti, Flavia, Russomanno, Pasquale, Novellino, Ettore, Montanari, Serena, Tumiatti, Vincenzo, Ballerini, Patrizia, Sarno, Federica, Nebbioso, Angela, Altucci, Lucia, Monti, Barbara, Andrisano, Vincenza, Milelli, Andrea, De Simone A, La Pietra V, Betari N, Petragnani N, Conte M, Daniele S, Pietrobono D, Martini C, Petralla S, Casadei R, Davani L, Frabetti F, Russomanno P, Novellino E, Montanari S, Tumiatti V, Ballerini P, Sarno F, Nebbioso A, Altucci L, Monti B, Andrisano V, Milelli A., De Simone, A., La Pietra, V., Betari, N., Petragnani, N., Conte, M., Daniele, S., Pietrobono, D., Martini, C., Petralla, S., Casadei, R., D'Avani, Paolo, Frabetti, F., Novellino, E., Montanari, S., Tumiatti, V., Ballerini, P., Sarno, F., Nebbioso, A., Altucci, L., Monti, B., Andrisano, ANGELA-MARIA, and Milelli, A.
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dual binding agents ,Polypharmacology, epigenetics, dual binding agents, glycogen synthase kinase 3β, histone deacetylases, neuroprotection ,Polypharmacology ,Disease ,01 natural sciences ,Biochemistry ,Neuroprotection ,GSK-3 ,Drug Discovery ,Epigenetics ,epigenetics ,glycogen synthase kinase 3β ,histone deacetylases ,neuroprotection ,biology ,010405 organic chemistry ,Chemistry ,Drug Discovery3003 Pharmaceutical Science ,Organic Chemistry ,Neurogenesis ,0104 chemical sciences ,Cell biology ,010404 medicinal & biomolecular chemistry ,Histone ,Cell culture ,Acetylation ,dual binding agent ,histone deacetylase ,biology.protein ,epigenetic - Abstract
[Image: see text] Several evidence pointed out the role of epigenetics in Alzheimer’s disease (AD) revealing strictly relationships between epigenetic and “classical” AD targets. Based on the reported connection among histone deacetylases (HDACs) and glycogen synthase kinase 3β (GSK-3β), herein we present the discovery and the biochemical characterization of the first-in-class hit compound able to exert promising anti-AD effects by modulating the targeted proteins in the low micromolar range of concentration. Compound 11 induces an increase in histone acetylation and a reduction of tau phosphorylation. It is nontoxic and protective against H(2)O(2) and 6-OHDA stimuli in SH-SY5Y and in CGN cell lines, respectively. Moreover, it promotes neurogenesis and displays immunomodulatory effects. Compound 11 shows no lethality in a wt-zebrafish model (
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- 2019
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125. Bio-guided fractionation of stem bark extracts from phyllanthus muellarianus: Identification of phytocomponents with anti-cholinesterase activity
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Marina Naldi, Caterina Temporini, Vincenza Andrisano, Manuela Bartolini, Gabriella Massolini, Gloria Brusotti, Naldi M., Brusotti G., Massolini G., Andrisano V., Temporini C., and Bartolini M.
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Phyllanthus ,Pharmaceutical Science ,Phyllanthus muellarianu ,Analytical Chemistry ,Plant Extract ,03 medical and health sciences ,chemistry.chemical_compound ,QD241-441 ,0302 clinical medicine ,Column chromatography ,Drug Discovery ,Bioassay ,Cholinesterase Inhibitor ,Solid phase extraction ,Physical and Theoretical Chemistry ,IC50 ,Phyllanthu ,030304 developmental biology ,Cholinesterase ,0303 health sciences ,Nitidine ,Chromatography ,biology ,Molecular Structure ,Organic Chemistry ,Anticholinesterase activity ,GPI-Linked Protein ,biology.organism_classification ,Molecular Docking Simulation ,chemistry ,Chemistry (miscellaneous) ,Anti-amyloid propertie ,Bioassay-guided fractionation ,Butyrylcholinesterase ,biology.protein ,Phyllanthus muellarianus ,Plant Bark ,Acetylcholinesterase ,Molecular Medicine ,Magnoflorine ,anti-amyloid properties ,030217 neurology & neurosurgery ,Human - Abstract
A combination of flash chromatography, solid phase extraction, high-performance liquid chromatography, and in vitro bioassays was used to isolate phytocomponents endowed with anticholinesterase activity in extract from Phyllanthus muellarianus. Phytocomponents responsible for the anti-cholinesterase activity of subfractions PMF1 and PMF4 were identified and re-assayed to confirm their activity. Magnoflorine was identified as an active phytocomponent from PMF1 while nitidine was isolated from PMF4. Magnoflorine was shown to be a selective inhibitor of human butyrylcholinesterase—hBChE (IC50 = 131 ± 9 μM and IC50 = 1120 ± 83 μM, for hBuChE and human acetylcholinesterase—hAChE, respectively), while nitidine showed comparable inhibitory potencies against both enzymes (IC50 = 6.68 ± 0.13 μM and IC50 = 5.31 ± 0.50 μM, for hBChE and hAChE, respectively). When compared with the commercial anti-Alzheimer drug galanthamine, nitidine was as potent as galanthamine against hAChE and one order of magnitude more potent against hBuChE. Furthermore, nitidine also showed significant, although weak, antiaggregating activity towards amyloid-β self-aggregation.
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- 2021
126. From virtual screening hits targeting a cryptic pocket in BACE-1 to a nontoxic brain permeable multitarget anti-Alzheimer lead with disease-modifying and cognition-enhancing effects
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Matthias Scheiner, Elsa M. Arce, María Isabel Loza, Marina Naldi, F. Javier Luque, Angela De Simone, Manuela Bartolini, Maria Laura Bolognesi, Michael Decker, Yolanda Soriano-Fernández, José Brea, Caterina Pont, Noemí Martínez, Diego Muñoz-Torrero, Alexia Mattellone, Belén Pérez, Marta Barenys, Raimon Sabaté, Jesús Gómez-Catalán, Christian Griñán-Ferré, Tiziana Ginex, Vincenza Andrisano, Mercè Pallàs, Pont C., Ginex T., Grinan-Ferre C., Scheiner M., Mattellone A., Martinez N., Arce E.M., Soriano-Fernandez Y., Naldi M., De Simone A., Barenys M., Gomez-Catalan J., Perez B., Sabate R., Andrisano V., Loza M.I., Brea J., Bartolini M., Bolognesi M.L., Decker M., Pallas M., Luque F.J., and Munoz-Torrero D.
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Zebra danio ,Peix zebra ,Drug Evaluation, Preclinical ,tau Proteins ,Alzheimer's disease ,Cryptic pocket ,Multitarget compound ,SAMP8 ,Zebrafish embryo ,Disease ,Molecular Dynamics Simulation ,Heterocyclic Compounds, 4 or More Rings ,chemistry.chemical_compound ,Structure-Activity Relationship ,Alzheimer Disease ,Drug Discovery ,Healthy control ,Aspartic Acid Endopeptidases ,Humans ,Pharmacology ,Virtual screening ,Anti alzheimer ,Amyloid beta-Peptides ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Envelliment cerebral ,Organic Chemistry ,Brain ,General Medicine ,Recombinant Proteins ,Cell biology ,Malaltia d'Alzheimer ,Neuroprotective Agents ,Tau phosphorylation ,Synaptophysin ,biology.protein ,Aging brain ,Aminoquinolines ,Amyloid Precursor Protein Secretases ,Lead compound - Abstract
Starting from six potential hits identified in a virtual screening campaign directed to a cryptic pocket of BACE-1, at the edge of the catalytic cleft, we have synthesized and evaluated six hybrid compounds, designed to simultaneously reach BACE-1 secondary and catalytic sites and to exert additional activities of interest for Alzheimer's disease (AD). We have identified a lead compound with potent in vitro activity towards human BACE-1 and cholinesterases, moderate Aβ42 and tau antiaggregating activity, and brain permeability, which is nontoxic in neuronal cells and zebrafish embryos at concentrations above those required for the in vitro activities. This compound completely restored short- and long-term memory in a mouse model of AD (SAMP8) relative to healthy control strain SAMR1, shifted APP processing towards the non-amyloidogenic pathway, reduced tau phosphorylation, and increased the levels of synaptic proteins PSD95 and synaptophysin, thereby emerging as a promising disease-modifying, cognition-enhancing anti-AD lead.
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- 2021
127. Development of an UHPLC-diode arrays detector (DAD) method for the analysis of polydatin in human plasma
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Vincenza Andrisano, A.V. Gaddi, Vincenzo Tumiatti, Lara Davani, M. Dimilta, A. De Simone, Serena Montanari, Montanari S., Davani L., Tumiatti V., Dimilta M., Gaddi A.V., De Simone A., and Andrisano V.
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Analyte ,Glucoside ,Metabolite ,Clinical Biochemistry ,Pharmaceutical Science ,Pharmacokinetic ,Reproducibility of Result ,Resveratrol ,01 natural sciences ,Analytical Chemistry ,chemistry.chemical_compound ,Plasma ,Pharmacokinetics ,Glucosides ,Ultra High Performance Liquid Chromatographic analysi ,Drug Discovery ,Stilbenes ,Humans ,Ultra High Performance Liquid Chromatographic analysis ,Spectroscopy ,Chromatography, High Pressure Liquid ,Diode ,Detection limit ,Chromatography ,010405 organic chemistry ,Polydatin ,Human plasma ,Reproducibility of Results ,010401 analytical chemistry ,Extraction (chemistry) ,Detector ,0104 chemical sciences ,chemistry ,High Pressure Liquid ,Human - Abstract
A new chromatographic method by Ultra High Performance Liquid Chromatographic (UHPLC) technology, has been developed and validated for the determination of polydatin and resveratrol, as potential metabolite, in human plasma. After the optimization of the chromatographic conditions, the method has been validated on spiked human plasma samples. The optimized extraction allowed to obtain analytes recovery up to 98.48 ± 4.03 %. Then, the isocratic elution in reversed phase mode, provides the separation of polydatin and resveratrol in less than 10.0 min. Chromatographic analysis was performed on a C18, 10 cm x 3.0 mm, 2.7 μm stationary phase, by using triethanolamine phosphate solution (0.1 M, pH = 3.7) and ACN 85:15 (v/v) as mobile phase at a flow rate of 0.5 mL/min. The UV detector was set at 306 nm for the analysis of both polydatin and resveratrol. The limit of detection (LoD) and the limit of quantification (LoQ) for polydatin in plasma samples were found to be 7.82 ± 0.38 nM and 26.06 ± 1.28 nM respectively. The method was found to be accurate and precise with a coefficient for intra- and inter-day variation below 5 %. All the reported data demonstrate how the developed method is rapid and sensitive. Moreover, results of the analysis of plasma samples, obtained from orally treated volunteers with nutritional supplements containing polydatin, have shown the method to be suitable for the pharmacokinetic characterization of polydatin and resveratrol, as metabolite, in humans.
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- 2021
128. Combined Methodologies for Determining In Vitro Bioavailability of Drugs and Prediction of In Vivo Bioequivalence From Pharmaceutical Oral Formulations
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Vincenza Andrisano, Lara Davani, F. Testi, S. Avanessian, A. De Simone, Vincenzo Tumiatti, Serena Montanari, De Simone A., Davani L., Montanari S., Tumiatti V., Avanessian S., Testi F., and Andrisano V.
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bioequivalence ,Chromatography ,levonorgestrel ,Chemistry ,drug–excipient interaction ,bioavailability ,dissolution model ,gastrointestinal passive permeability ,PAMPA ,Excipient ,Absorption (skin) ,General Chemistry ,Bioequivalence ,Permeation ,Bioavailability ,In vivo ,medicine ,Dissolution testing ,QD1-999 ,Dissolution ,medicine.drug ,Original Research - Abstract
With the aim of developing an in vitro model for the bioavailability (BA) prediction of drugs, we focused on the study of levonorgestrel (LVN) released by 1.5 mg generic and brand-name tablets. The developed method consisted in combining a standard dissolution test with an optimized parallel artificial membrane permeability assay (PAMPA) to gain insights into both drug release and gastrointestinal absorption. Interestingly, the obtained results revealed that the tablet standard dissolution test, combined with an optimized PAMPA, highlighted a significant decrease in the release (15 ± 0.01 μg min−1 vs 30 ± 0.01 μg min−1) and absorption (19 ± 7 × 10–6 ± 7 cm/s Pe vs 41 ± 15 × 10–6 cm/s Pe) profiles of a generic LVN tablet when compared to the brand-name formulation, explaining unbalanced in vivo bioequivalence (BE). By using this new approach, we could determine the actual LVN drug concentration dissolved in the medium, which theoretically can permeate the gastrointestinal (GI) barrier. In fact, insoluble LVN/excipient aggregates were found in the dissolution media giving rise to non-superimposable dissolution profiles between generic and brand-name LVN tablets. Hence, the results obtained by combining the dissolution test and PAMPA method provided important insights confirming that the combined methods can be useful in revealing crucial issues in the prediction of in vivo BE of drugs.
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- 2021
129. (±)- BIGI-3h: Pentatarget-Directed Ligand combining Cholinesterase, Monoamine Oxidase, and Glycogen Synthase Kinase 3β Inhibition with Calcium Channel Antagonism and Antiaggregating Properties for Alzheimer's Disease
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Vendula Hepnarova, Kamil Musilek, Aurélie Baguet, Daniel Jun, José Marco-Contelles, Lhassane Ismaili, Emmanuel Haffen, Tomas Kucera, Jan Korabecny, Jana Janockova, Angela De Simone, Eva M. García-Frutos, Vincenza Andrisano, Manuela Bartolini, B. Refouvelet, Lucía Viejo, Cristóbal de los Ríos, Adeline Etievant, Ondrej Soukup, Rudolf Andrys, Julie Monnin, Raquel L Arribas, Conseil régional of Franche-Comté, Czech Science Foundation, Ministry of Education, Youth and Sports (Czech Republic), Ismaili L., Monnin J., Etievant A., Arribas R.L., Viejo L., Refouvelet B., Soukup O., Janockova J., Hepnarova V., Korabecny J., Kucera T., Jun D., Andrys R., Musilek K., Baguet A., Garcia-Frutos E.M., De Simone A., Andrisano V., Bartolini M., De Los Rios C., Marco-Contelles J., and Haffen E.
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cholinesterase ,Physiology ,Monoamine oxidase ,Cognitive Neuroscience ,Ligand ,Pharmacology ,Ligands ,Calcium Channel ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,In vivo ,GSK-3 ,Humans ,Cholinesterases ,Cholinesterase Inhibitor ,Biginelli reaction ,Alzheimer's disease ,calcium channel ,cholinesterases ,GSK 3β ,MAO ,Calcium Channel Blockers ,Calcium Channels ,Cholinesterase Inhibitors ,Glycogen Synthase Kinase 3 beta ,Monoamine Oxidase ,GSK3B ,030304 developmental biology ,Cholinesterase ,0303 health sciences ,Voltage-dependent calcium channel ,biology ,Chemistry ,Calcium channel ,Cell Biology ,General Medicine ,Calcium channel, GSK 3β, MAO ,biology.protein ,Monoamine oxidase A ,Calcium Channel Blocker ,Alzheimer’s disease ,030217 neurology & neurosurgery ,Human - Abstract
Multitarget-directed ligands (MTDLs) are considered a promising therapeutic strategy to address the multifactorial nature of Alzheimer's disease (AD). Novel MTDLs have been designed as inhibitors of human acetylcholinesterases/butyrylcholinesterases, monoamine oxidase A/B, and glycogen synthase kinase 3β and as calcium channel antagonists via the Biginelli multicomponent reaction. Among these MTDLs, (±)-BIGI-3h was identified as a promising new hit compound showing in vitro balanced activities toward the aforementioned recognized AD targets. Additional in vitro studies demonstrated antioxidant effects and brain penetration, along with the ability to inhibit the aggregation of both τ protein and β-amyloid peptide. The in vivo studies have shown that (±)-BIGI-3h (10 mg/kg intraperitoneally) significantly reduces scopolamine-induced cognitive deficits., L.I. thanks the Regional Council of Franche-Comté (2016YC- 04540 and 04560) for financial support, Mrs. M.-J. Henriot (PHV Pharma) for her support in the HPLC analyses, and Vincent Luzet for preliminary results in synthesis. O.S., J.J., and J.K. acknowledge the support from the grant by Czech Science Foundation no. 20-29633J. T.K., D.J., and V.H. acknowledge support from the Long-term Development Plan (Faculty of Military Health Sciences). R.A. and K.M. thank the Ministry of Education, Youth and Sports of the Czech Republic (ERDF no. CZ.02.1.01/0.0/0.0/16_025/0007444).
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- 2021
130. Indole derivative interacts with estrogen receptor beta and inhibits human ovarian cancer cell growth
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Carla Boga, Marina Naldi, Jessica Fiori, Vincenza Andrisano, Laura Verardi, Elena Strocchi, Carlo Bertucci, Natalia Calonghi, Rita Morigi, Gabriele Micheletti, Alessandra Locatelli, Verardi L., Fiori J., Andrisano V., Locatelli A., Morigi R., Naldi M., Bertucci C., Strocchi E., Boga C., Micheletti G., and Calonghi N.
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Indoles ,endocrine system diseases ,Pharmaceutical Science ,Article ,Analytical Chemistry ,Metastasis ,lcsh:QD241-441 ,03 medical and health sciences ,0302 clinical medicine ,Cyclin D1 ,lcsh:Organic chemistry ,CDKN2A ,Ovarian cancer ,Cell Line, Tumor ,histones ,Drug Discovery ,medicine ,Humans ,Estrogen receptor beta ,Physical and Theoretical Chemistry ,030304 developmental biology ,Cell Proliferation ,Ovarian Neoplasms ,LC/ESI/MS ,0303 health sciences ,biology ,Chemistry ,Cell growth ,Chromatin binding ,Organic Chemistry ,medicine.disease ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,Molecular Docking Simulation ,Histone ,Chemistry (miscellaneous) ,030220 oncology & carcinogenesis ,Molecular docking ,biology.protein ,Cancer research ,Molecular Medicine ,Indole derivative ,Female - Abstract
Ovarian cancer remains the leading cause of mortality among gynecological tumors. Estrogen receptor beta (ER&beta, ) expression has been suggested to act as a tumor suppressor in epithelial ovarian cancer by reducing both tumor growth and metastasis. ER&beta, expression abnormalities represent a critical step in the development and progression of ovarian cancer: for these reasons, its re-expression by genetic engineering, as well as the use of targeted ER&beta, therapies, still constitute an important therapeutic approach. 3-{[2-chloro-1-(4-chlorobenzyl)-5-methoxy-6-methyl-1H-indol-3-yl]methylene}-5-hydroxy-6-methyl-1,3-dihydro-2H-indol-2-one, referred to here as compound 3, has been shown to have cytostatic as well cytotoxic effects on various hormone-dependent cancer cell lines. However, the mechanism of its anti-carcinogenic activity is not well understood. Here, we offer a possible explanation of such an effect in the human ovarian cancer cell line IGROV1. Chromatin binding protein assay and liquid chromatography mass spectrometry were exploited to localize and quantify compound 3 in cells. Molecular docking was used to prove compound 3 binding to ER&beta, Mass spectrometry-based approaches were used to analyze histone post-translational modifications. Finally, gene expression analyses revealed a set of genes regulated by the ER&beta, /3 complex, namely CCND1, MYC, CDKN2A, and ESR2, providing possible molecular mechanisms that underline the observed antiproliferative effects.
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- 2020
131. Targeting topoisomerase II with trypthantrin derivatives: Discovery of 7-((2-(dimethylamino)ethyl)amino)indolo[2,1-b]quinazoline-6,12-dione as an antiproliferative agent and to treat cancer
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Vincenza Andrisano, Carmela Fimognari, Vincenzo Tumiatti, Marco B. L. Rocchi, Alan Santini, Dmitri V. Krysko, Ivano Vassura, Marco De Vivo, Serena Montanari, Jose M. Arencibia, Nibal Betari, Elena Catanzaro, Andrea Milelli, Angela De Simone, Claudia Sissi, Catanzaro E., Betari N., Arencibia J.M., Montanari S., Sissi C., De Simone A., Vassura I., Santini A., Andrisano V., Tumiatti V., De Vivo M., Krysko D.V., Rocchi M.B.L., Fimognari C., and Milelli A.
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Drug ,Cell Survival ,media_common.quotation_subject ,Tryptanthrin ,Antineoplastic Agents ,01 natural sciences ,Drug design ,Anticancer agents ,Topoisomerase II ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Discovery ,Tumor Cells, Cultured ,medicine ,Quinazoline ,Humans ,Topoisomerase II Inhibitors ,IC50 ,Etoposide ,Cell Proliferation ,030304 developmental biology ,media_common ,Pharmacology ,0303 health sciences ,Natural product ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,010405 organic chemistry ,Chemistry ,Drug discovery ,Topoisomerase ,Organic Chemistry ,Cancer ,General Medicine ,medicine.disease ,0104 chemical sciences ,DNA Topoisomerases, Type II ,Anticancer agent ,biology.protein ,Cancer research ,Drug Screening Assays, Antitumor ,medicine.drug - Abstract
Drugs targeting human topoisomerase II (topoII) are used in clinical practice since decades. Nevertheless, there is an urgent need for new and safer topoII inhibitors due to the emergence of secondary malignancies and the appearance of resistance mechanisms upon treatment with topoII-targeted anticancer drugs. In the present investigation, we report the discovery of a new topoII inhibitor, whose design was based on the structure of the natural product trypthantrin, a natural alkaloid containing a basic indoloquinazoline moiety. This new topoII inhibitor, here numbered compound 5, is found to inhibit topoII with an IC50 of 26.6 ± 4.7 μM. Notably, compound 5 is more potent than the template compound trypthantrin, and even than the widely used topoII-targeted clinical drug etoposide. In addition, compound 5 also exhibits high water solubility, and a promising antiproliferative activity on different tumor cell lines such as acute leukemia, colon, and breast cancer. In light of these results, compound 5 represents a promising lead for developing new topoII inhibitors as anti-cancer therapeutic agents.
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- 2020
132. Advanced analytical methodologies in Alzheimer's disease drug discovery
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Marina Naldi, Manuela Bartolini, Lara Davani, Vincenza Andrisano, Daniele Tedesco, Angela De Simone, De Simone A., Naldi M., Tedesco D., Bartolini M., Davani L., and Andrisano V.
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Clinical Biochemistry ,Tau protein ,Pharmaceutical Science ,Spectroscopie ,Computational biology ,01 natural sciences ,Chemistry Techniques, Analytical ,Analytical Chemistry ,Alzheimer Disease ,Microscopies ,Drug Discovery ,medicine ,Animals ,Humans ,Cholinesterases ,Hit selection ,Surface plasmon resonance ,Microscopie ,Spectroscopy ,biology ,Mass spectrometry ,010405 organic chemistry ,Mechanism (biology) ,Chemistry ,Drug discovery ,010401 analytical chemistry ,Neurodegeneration ,BACE1 ,Alzheimer's disease ,Cholinesterase ,medicine.disease ,High-Throughput Screening Assays ,0104 chemical sciences ,Förster resonance energy transfer ,biology.protein ,Amyloid beta peptide ,Spectroscopies ,Amyloid precursor protein secretase - Abstract
Accepted Manuscript version. The Published Journal Article is available on the Journal of Pharmaceutical and Biomedical Analysis, Volume 178, Article number 112899 (DOI: https://doi.org/10.1016/j.jpba.2019.112899). Supplementary Material available free of charge on the article webpage. © 2020. This Manuscript version is made available under the CC-BY-NC-ND 4.0 license. https://creativecommons.org/licenses/by-nc-nd/4.0/ ABSTRACT Despite the constant progress in the understanding of the etiopathogenesis of Alzheimer’s disease (AD) over the last 50 years, just four long-standing drugs are currently used for AD therapy. This article reviews the analytical methodologies developed and applied in the last five years to address the early-stage tasks of the AD drug discovery process: the fast selection of active compounds (hits) and the comprehension of the ligand binding mechanism of the compound chosen to be the lead in the forthcoming development. The reviewed analytical methodologies face the most investigated pharmacological protein targets (amyloids, secretases, kinases, cholinesterases) and specific receptor- and enzyme-mediated effects in neurotransmission, neuroprotection and neurodegeneration. Some of these methodologies are noteworthy for their use in middle/high-throughput screening campaigns during hit selection (e.g. surface plasmon resonance biosensing, fluorescence resonance energy transfer assays), whereas some others (circular dichroism and nuclear magnetic resonance spectroscopies, ion mobility–mass spectrometry) can provide in-depth information about the structure, conformation and ligand binding properties of target proteins.
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- 2020
133. Drug affinity to immobilized target bio-polymers by high-performance liquid chromatography and capillary electrophoresis
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Bertucci, C., Bartolini, M., Gotti, R., and Andrisano, V.
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DRUGS , *HIGH performance liquid chromatography , *AFFINITY electrophoresis , *POLYMERS , *CAPILLARY electrophoresis , *CHIRAL drugs , *SEPARATION (Technology) , *IMMOBILIZED proteins - Abstract
This review addresses the use of high-performance liquid chromatography (HPLC) and capillary electrophoresis (CE) as affinity separation methods to characterise drugs or potential drugs–bio-polymer interactions. Targets for the development of new drugs such as enzymes (IMERs), receptors, and membrane proteins were immobilized on solid supports. After the insertion in the HPLC system, these immobilized bio-polymers were used for the determination of binding constants of specific ligands, substrates and inhibitors of pharmaceutical interest, by frontal analyses and zonal elution methods. The most used bio-polymer immobilization techniques and methods for assessing the amount of active immobilized protein are reported. Examples of increased stability of immobilized enzymes with reduced amount of used protein were shown and the advantages in terms of recovery for reuse, reproducibility and on-line high-throughput screening for potential ligands are evidenced. Dealing with the acquisition of relevant pharmacokinetic data, examples concerning human serum albumin binding studies are reviewed. In particular, papers are reported in which the serum carrier has been studied to monitor the enantioselective binding of chiral drugs and the mutual interaction between co-administered drugs by CE and HPLC. Finally CE, as merging techniques with very promising and interesting application of microscale analysis of drugs’ binding parameters to immobilized bio-polymers is examined. [Copyright &y& Elsevier]
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- 2003
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134. Determination of the dissociation constants (pKa) of basic acetylcholinesterase inhibitors by reversed-phase liquid chromatography
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Bartolini, M., Bertucci, C., Gotti, R., Tumiatti, V., Cavalli, A., Recanatini, M., and Andrisano, V.
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DISSOCIATION (Chemistry) , *ACETONITRILE , *REGRESSION analysis - Abstract
An RP-HPLC study for the pKa determination of a series of basic compounds related to caproctamine, a dibenzylamine-diamide reversible inhibitor of acetylcholinesterase, is reported. The 2-substituted analogues, bearing substituents with different electronegativity, were analysed by RP-HPLC by using C18, C4 stationary phases with a mobile phase consisting of mixture of acetonitrile and triethylamine phosphate buffer (pH range comprised between 4 and 10). Typical sigmoidal curves were obtained, showing the dependence of the capacity factors upon pH. In general, the retention of the investigated basic analytes increased with increasing of the pH. The inflection point of the pH sigmoidal dependence was used for the dissociation constant determination at a fixed acetonitrile percentage. When plotting pKa vs. percent of acetonitrile in the mobile phase for two representative compounds, linear regression were obtained: the y intercept gave the aqueous pKa(w). The pKa estimation by HPLC method was found to be useful to underline the difference of benzylamine basicity produced by the ortho aromatic substituents. The variation of pKa values (6.15–7.80) within the series of compounds was correlated with the electronic properties of the ortho-substituents through the Hammett σ parameter, whereas the ability of substituents to accept H-bond was found to play a role in determining the conformational behavior of the molecules. [Copyright &y& Elsevier]
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- 2002
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135. Multifunctional activity of some isoquinoline alkaloids from Corydalis cava tubers on Alzheimer's disease targets
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Lubomír Opletal, Jakub Chlebek, Concepción Pérez, Lucie Havlíková, A. De Simone, Anna Hošťálková, Lucie Cahlíková, Vincenza Andrisano, DI Pérez, Chlebek, J, De Simone, A, Pérez, Di, Pérez, C, Havlíková, L, Hošťálková, A, Opletal, L, Cahlíková, L, and Andrisano, V
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Pharmacology ,Traditional medicine ,business.industry ,Organic Chemistry ,Pharmaceutical Science ,BACE1 ,Corydalis cava alkaloids ,Analytical Chemistry ,chemistry.chemical_compound ,Complementary and alternative medicine ,chemistry ,Corydalis cava ,immobilized enzyme reactor ,PAMPA assay ,Drug Discovery ,BACE1, immobilized enzyme reactor, Corydalis cava alkaloids, PAMPA assay ,Molecular Medicine ,Medicine ,Isoquinoline ,business - Abstract
Fifteen previously isolated Corydalis cava alkaloids have been investigated for their potential multifunctional activity on Alzheimer's disease (AD) targets. Determination of ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibition was carried out using a BACE1-Immobilized Enzyme Reactor (IMER) by validating the assay with a multi-well plate format Fluorescence Resonance Energy Transfer (FRET) assay. Seven alkaloids out of fifteen were found to be active, (-)-corycavamine (IC50 FRET= 41.16 ± 7.82µM; IC50 IMER= 1690 ± 545.0µM) and (+)-corynoline (IC50 FRET = 33.59 ± 0.23µM; IC50 IMER = 89.07 ± 15.08µM) demonstrated the highest BACE1 inhibition activity, in the micromolar range, in a concentration dependent manner. BACE1-IMER was found to be a valid device for the fast screening of inhibitors and the determination of their potency. In a permeation assay (PAMPA) for the prediction of blood-brain barrier (BBB) penetration, the most active compounds (-)-corycavamine (Pe = 16.3 ± 0.9 × 10-6 cm s-1) and (+)-corynoline (Pe = 11.7 ± 0.1 × 10-6 cm s-1) were found to be able to cross the BBB. Not all compounds showed activity against glycogen synthase kinase-3β (GSK-3β) and casein kinase-1δ (CK-1δ). Furthermore, on the basis of the reported results, we found that some Corydalis cava alkaloids have multifunctional activity against AD targets (prolyl oligopeptidase, cholinesterases, and BACE1). Moreover, we tried to elucidate the treatment effectivity (rational use) of its extract in memory dysfunction in folk medicine. Based on a HPLC-UV analysis we found that due to quantitative low content of compounds with neuroprotective activity in the plant material, the use of C. cava extracts in the therapy of memory dysfunction in folk medicine is not corroborated by ascertained data .
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- 2016
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136. Site-specific quantification of lysine acetylation in the N-terminal tail of histone H4 using a double-labelling, targeted UHPLC MS/MS approach
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Thea van den Bosch, Alexander P. Boichenko, Annalisa D’Urzo, Frank J. Dekker, Vincenza Andrisano, Jos Hermans, Rainer Bischoff, Chemical and Pharmaceutical Biology, Analytical Biochemistry, Biopharmaceuticals, Discovery, Design and Delivery (BDDD), Medicinal Chemistry and Bioanalysis (MCB), D'Urzo, A, Boichenko, Ap, van den Bosch, T, Hermans, J, Dekker, F, Andrisano, V, and Bischoff, R.
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0301 basic medicine ,Tandem mass spectrometry ,DEACETYLASE INHIBITORS ,Lysine ,Histone deacetylase (HDAC) inhibitors ,Histone deacetylase (HDAC) inhibitor ,Biochemistry ,Cell Line ,Analytical Chemistry ,Histones ,Histone H4 ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Animals ,Amino Acid Sequence ,Post-translation modification (PTM) ,Derivatization ,Chromatography, High Pressure Liquid ,PROPIONYLATION ,Chymotrypsin ,Chromatography ,biology ,Reproducibility of Results ,Acetylation ,MASS-SPECTROMETRY ,MS ,Trypsin ,ALZHEIMERS-DISEASE ,Histone Deacetylase Inhibitors ,030104 developmental biology ,Histone acetylation ,chemistry ,Multiple reaction monitoring (MRM) ,biology.protein ,Histone deacetylase ,030217 neurology & neurosurgery ,Research Paper ,medicine.drug - Abstract
We developed a targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the site-specific quantification of lysine acetylation in the N-terminal region of histone H4 by combining chemical derivatization at the protein and peptide levels with digestion using chymotrypsin and trypsin. Unmodified ε-amino groups were first modified with propionic acid anhydride and the derivatized protein digested with trypsin and chymotrypsin. The newly formed peptide N-termini were subjected to a second derivatization step with d6- (heavy) or d0- (light) acetic acid anhydride. Samples were mixed at different ratios and peptides monitored by multiple reaction monitoring (MRM) LC-MS/MS. The method was validated in terms of linearity (R2 ≥ 0.94), precision (RSD ≤ 10 %), and accuracy (≤27 %) and used to assess the effect of the histone deacetylase (HDAC) inhibitors SAHA and MS-275 in the murine macrophage-like cell line RAW 264.7. SAHA and MS-275 showed site-specific effects on the acetylation levels of K5 and K8 with the K5(Ac)–K8 and K5–K8(Ac) peptides increasing 2.5-fold and 5-fold upon treatment with SAHA and MS-275, respectively. Assessing lysine acetylation in a site-specific manner is important for gaining a better understanding of the effects of HDAC inhibitors and for clarifying disease mechanisms where lysine acetylation plays a role. Electronic supplementary material The online version of this article (doi:10.1007/s00216-016-9431-1) contains supplementary material, which is available to authorized users.
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- 2016
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137. A novel class of multitarget anti-Alzheimer benzohomoadamantane‒chlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors
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Santiago Vázquez, Deborah Pivetta, Vincenza Andrisano, Diego Muñoz-Torrero, Andreea L. Turcu, Belén Pérez, Alba Espargaró, F. Javier Pérez-Areales, Caterina Pont, Angela De Simone, Raimon Sabaté, Francesc X. Sureda, Manuela Bartolini, Marta Barniol-Xicota, Perez-Areales F.J., Turcu A.L., Barniol-Xicota M., Pont C., Pivetta D., Espargaro A., Bartolini M., De Simone A., Andrisano V., Perez B., Sabate R., Sureda F.X., Vazquez S., Munoz-Torrero D., and Universitat de Barcelona
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Multi-target-directed ligands ,NMDA antagonists ,Química farmacèutica ,Adamantane ,Pharmacology ,01 natural sciences ,chemistry.chemical_compound ,Drug Discovery ,Cholinesterase Inhibitor ,Butyrylcholinesterase ,Butyrylcholinesterase inhibitors ,0303 health sciences ,Molecular Structure ,Chemistry ,Butyrylcholinesterase inhibitor ,Malalties neurodegeneratives ,Memantine ,Neurodegenerative Diseases ,General Medicine ,Alzheimer's disease ,Cerebral cortex ,Acetylcholinesterase inhibitors ,Brain permeability ,Multitarget compounds ,Acetylcholinesterase ,Escorça cerebral ,Neuroprotective Agents ,Tacrine ,NMDA receptor ,medicine.drug ,Human ,Neuroprotective Agent ,NMDA antagonist ,Receptors, N-Methyl-D-Aspartate ,03 medical and health sciences ,Structure-Activity Relationship ,Alzheimer Disease ,Multi-target-directed ligand ,medicine ,Potency ,Structure–activity relationship ,Humans ,IC50 ,030304 developmental biology ,Dose-Response Relationship, Drug ,010405 organic chemistry ,Organic Chemistry ,0104 chemical sciences ,Malaltia d'Alzheimer ,Acetylcholinesterase inhibitor ,Multitarget compound ,Cholinesterase Inhibitors ,Pharmaceutical chemistry - Abstract
The development of multitarget compounds against multifactorial diseases, such as Alzheimer's disease, is an area of very intensive research, due to the expected superior therapeutic efficacy that should arise from the simultaneous modulation of several key targets of the complex pathological network. Here we describe the synthesis and multitarget biological profiling of a new class of compounds designed by molecular hybridization of an NMDA receptor antagonist fluorobenzohomoadamantanamine with the potent acetylcholinesterase (AChE) inhibitor 6-chlorotacrine, using two different linker lengths and linkage positions, to preserve or not the memantine-like polycyclic unsubstituted primary amine. The best hybrids exhibit greater potencies than parent compounds against AChE (IC50 0.33 nM in the best case, 44-fold increased potency over 6-chlorotacrine), butyrylcholinesterase (IC50 21 nM in the best case, 24-fold increased potency over 6-chlorotacrine), and NMDA receptors (IC50 0.89 μM in the best case, 2-fold increased potency over the parent benzohomoadamantanamine and memantine), which suggests an additive effect of both pharmacophoric moieties in the interaction with the primary targets. Moreover, most of these compounds have been predicted to be brain permeable. This set of biological properties makes them promising leads for further anti-Alzheimer drug development.
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- 2019
138. Amaryllidaceae alkaloids from Narcissus pseudonarcissus L. cv. Dutch Master as potential drugs in treatment of Alzheimer's disease
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Anna Hošťálková, Jakub Chlebek, Lubomír Opletal, Vincenza Andrisano, Jana Maříková, Jiří Kuneš, Daniela Hulcová, Jan Korábečný, Aleš Růžička, Daniel Jun, Lucie Nováková, Angela De Simone, Lucie Cahlíková, Hulcova D., Marikova J., Korabecny J., Hostalkova A., Jun D., Kunes J., Chlebek J., Opletal L., De Simone A., Novakova L., Andrisano V., Ruzicka A., and Cahlikova L.
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0106 biological sciences ,Cholinesterase inhibition ,Amaryllidaceae Alkaloid ,Oligopeptidase ,Plant Science ,01 natural sciences ,Biochemistry ,chemistry.chemical_compound ,Glycogen synthase kinase-3β inhibition ,Alkaloid ,Cholinesterase Inhibitor ,heterocyclic compounds ,Butyrylcholinesterase ,Narcissus pseudonarcissus L. cv. Dutch master ,biology ,Traditional medicine ,Molecular Structure ,Chemistry ,Serine Endopeptidases ,Narcissus ,General Medicine ,Alzheimer's disease ,Acetylcholinesterase ,Serine Endopeptidase ,Neuroprotective Agents ,Prolyl oligopeptidase ,Drug ,Prolyl Oligopeptidases ,Human ,Neuroprotective Agent ,Horticulture ,Dose-Response Relationship ,Structure-Activity Relationship ,Alkaloids ,Alzheimer Disease ,Structure–activity relationship ,Humans ,Amaryllidaceae Alkaloids ,Molecular Biology ,Amaryllidaceae ,Narcimatuline ,Cholinesterase Inhibitors ,Dose-Response Relationship, Drug ,Glycogen Synthase Kinase 3 beta ,010405 organic chemistry ,biology.organism_classification ,Narcissu ,0104 chemical sciences ,010606 plant biology & botany - Abstract
Twenty-one known Amaryllidaceae alkaloids of various structural types and one undescribed alkaloid, named narcimatuline, have been isolated from fresh bulbs of Narcissus pseudonarcissus L. cv. Dutch Master. The chemical structures were elucidated by combination of MS, HRMS, 1D and 2D NMR spectroscopic techniques, and by comparison with literature data. Narcimatuline amalgamates two basic scaffolds of Amaryllidaceae alkaloids in its core, namely galanthamine and galanthindole. All isolated compounds were evaluated for their in vitro acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), prolyl oligopeptidase (POP), and glycogen synthase kinase-3β (GSK-3β) inhibitory activities. The most interesting biological profile was demonstrated by newly isolated alkaloid narcimatuline.
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- 2019
139. Isoquinoline alkaloids from berberis vulgaris as potential lead compounds for the treatment of alzheimer's disease
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Vincenza Andrisano, Daniel Jun, Jan Korabecny, Jana Marikova, Daniel I. Perez, Lucie Nováková, Tomas Kucera, Lucie Cahlíková, Tomáš Siatka, Jiri Kunes, Daniela Hulcová, Lubomír Opletal, Anna Hošt'álková, Hostalkova A., Marikova J., Opletal L., Korabecny J., Hulcova D., Kunes J., Novakova L., Perez D.I., Jun D., Kucera T., Andrisano V., Siatka T., and Cahlikova L.
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Berberis ,Magnetic Resonance Spectroscopy ,Stereochemistry ,Plant Exudates ,Pharmaceutical Science ,Oligopeptidase ,Berbamine ,01 natural sciences ,Analytical Chemistry ,chemistry.chemical_compound ,Alkaloids ,Alzheimer Disease ,Drug Discovery ,Humans ,Isoquinoline ,IC50 ,Butyrylcholinesterase ,Pharmacology ,010405 organic chemistry ,Organic Chemistry ,Isoquinoline alkaloids, lead compounds, alzheimer's disease ,Nuclear magnetic resonance spectroscopy ,Isoquinolines ,Acetylcholinesterase ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Complementary and alternative medicine ,chemistry ,Blood-Brain Barrier ,Molecular Medicine ,Cholinesterase Inhibitors ,Two-dimensional nuclear magnetic resonance spectroscopy - Abstract
Three new alkaloids, bersavine (3), muraricine (4), and berbostrejdine (8), together with seven known isoquinoline alkaloids (1-2, 5-7, 9, and 10) were isolated from an alkaloidal extract of the root bark of Berberis vulgaris. The structures of the isolated compounds were determined by spectroscopic methods, including 1D and 2D NMR techniques, HRMS, and optical rotation, and by comparison of the obtained data with those in the literature. The NMR data of berbamine (5), aromoline (6), and obamegine (7) were completely assigned employing 2D NMR experiments. Alkaloids isolated in sufficient amounts were evaluated for their in vitro acetylcholinesterase, butyrylcholinesterase (BuChE), prolyl oligopeptidase, and glycogen synthase kinase-3β inhibitory activities. Selected compounds were studied for their ability to permeate through the blood-brain barrier. Significant human BuChE ( hBuChE) inhibitory activity was demonstrated by 6 (IC50 = 0.82 ± 0.10 μM). The in vitro data were further supported by computational analysis that showed the accommodation of 6 in the active site of hBuChE.
- Published
- 2019
140. Development of an UHPLC-diode arrays detector (DAD) method for the analysis of polydatin in human plasma.
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Montanari, S., Davani, L., Tumiatti, V., Dimilta, M., Gaddi, A.V., De Simone, A., and Andrisano, V.
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CHROMATOGRAPHIC analysis , *DETECTORS , *RESVERATROL , *DETECTION limit , *HUMAN beings , *BIOAVAILABILITY , *DIETARY supplements - Abstract
[Display omitted] • Development and validation of UHPLC analytical method for the characterization of polydatin bioavailability. • Average recovery higher than 98 %. • Sensitivity in the nanomolar range. • Fast detection and separation of polydatin and resveratrol in human plasma and urine. • Application of the method for pharmacokinetic characterization of dietary supplements in human. A new chromatographic method by Ultra High Performance Liquid Chromatographic (UHPLC) technology, has been developed and validated for the determination of polydatin and resveratrol, as potential metabolite, in human plasma. After the optimization of the chromatographic conditions, the method has been validated on spiked human plasma samples. The optimized extraction allowed to obtain analytes recovery up to 98.48 ± 4.03 %. Then, the isocratic elution in reversed phase mode, provides the separation of polydatin and resveratrol in less than 10.0 min. Chromatographic analysis was performed on a C18, 10 cm x 3.0 mm, 2.7 μm stationary phase, by using triethanolamine phosphate solution (0.1 M, pH = 3.7) and ACN 85:15 (v/v) as mobile phase at a flow rate of 0.5 mL/min. The UV detector was set at 306 nm for the analysis of both polydatin and resveratrol. The limit of detection (LoD) and the limit of quantification (LoQ) for polydatin in plasma samples were found to be 7.82 ± 0.38 nM and 26.06 ± 1.28 nM respectively. The method was found to be accurate and precise with a coefficient for intra- and inter-day variation below 5 %. All the reported data demonstrate how the developed method is rapid and sensitive. Moreover, results of the analysis of plasma samples, obtained from orally treated volunteers with nutritional supplements containing polydatin, have shown the method to be suitable for the pharmacokinetic characterization of polydatin and resveratrol, as metabolite, in humans. [ABSTRACT FROM AUTHOR]
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- 2021
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141. The role of Chromatography in Alzheimer’s Disease Drug Discovery
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FIORI, JESSICA, DE SIMONE, ANGELA, NALDI, MARINA, ANDRISANO, VINCENZA, Fiori, J, De Simone, A, Naldi, M, and Andrisano, V
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Hit selection ,Imer ,biomarkers ,pharmacokinetis ,Hit selection, Imer, biomarkers, pharmacokinetis - Abstract
Alzheimer’s disease (AD), the most common form of dementia in adults, is a neurodegenerative disorder whose physiopathological events include progressive cognitive impairment and memory loss, associated with a deficit in cholinergic neurotransmission (Davies and Maloney 1976). Histological hallmarks that characterize this disorder comprise plaques of β-amyloid (Aβ) peptide, neurofibrillary tangles (NFT), a dramatic loss of synapses and neurons, and a decreased level of choline acetyltransferase that correlates with a decline in mental status scores (Bartus et al., 1982). This disease is still a serious burden for the society, since no effective pharmacological treatment has yet been found. The only symptomatic drugs being available on the market can just partially restore the cholinergic deficit in the first stages of the disease. Therefore, the research is strongly focused on the discovery of new effective drugs which can halt and reverse the disease. Owing to the multi-factorial nature of AD, one of the most promising drug discovery approaches for AD treatment is addressed to compounds with a multitarget biological profile, the so-called multitarget-directed ligands (MTDLs) (Cavalli et al., 2008). MTDLs developed so far include derivatives that can simultaneously restore brain acetylcholine (ACh) levels, decrease oxidative stress, inhibit Aβ aggregation and formation, decrease tau protein hyperphosphorylation and protect neuronal cells against toxic insults (Prati et al., 2015). The research efforts in drug discovery field are based on the knowledge of the molecular aspects of the disease and on the development of new techniques necessary to investigate the biological systems at molecular level. The selection of new leads to enter clinical trials is therefore a challenging task and involve various essential steps, the first being the selection of molecules able to bind to the AD validated target(s), and then the study of the effects of hitting the target at molecular, cellular, whole animal and human level. In the case of Alzheimer’s disease (AD), acetylcholinesterase (AChE) has been the first target for the development of new drugs since the discovery of the cholinergic deficit in the central nervous system. However, basic research showed that cognitive impairment could be due not only to a cholinergic deficit but also to a cascade of biochemical events leading to the accumulation in the brain of proteins such as ß-amyloid (A) and hyper-phosphorylated tau protein. Important targets are amyloid fibrillogenesis, beta-secretase amyloid precursor protein cleaving enzyme (BACE1), one of the enzymes which cleave APP (amyloid precursor protein) and GSK3, a tau protein phosphorylating kinase. On the other hand, other non cholinergic role of AChE in the AD has been discovered: some evidences suggest that AChE peripheral binding site may play a key role in the development of senile plaques, accelerating A deposition. Once the disease targets have been selected, the determination of the activity of the new compounds must be carried out quickly and in a way that allows the verification of the design hypothesis. Drug activity is in fact mediated by different types of interactions with specific biological targets and the esteem of these interactions may elucidate the mechanism of action. To this aim, in a first instance, high throughput screening methods (HTS) of a large number of compounds for the selection of few lead compounds are required. Secondly, specific methods, which elucidate the selected compound mechanism of action in vitro, have to be employed, before the ultimate and most advanced tools, transgenic animal models of the disease, can be used to study the effects of single compounds on the disease phenotype in vivo, followed by clinical trials on real patients. Towards all these aims, separation science is a demand and a resource for solving the urging analytical problems associated with all the steps in the long pathways which go from the selection of active compounds to the complete development of new drugs. Here we review the purposely designed chromatographic methodologies which have contributed in defining the most important steps towards the discovery of new drugs for AD. To start with, an important contribution is given by in vitro assessment of the activity of chemical libraries on isolated target by the affinity chromatography on HPLC immobilized-enzyme column (or immobilized enzyme reactors, IMERs). A further step is the in vivo verification of activity of the lead selected compound by monitoring the appropriate biomarkers in biological fluids in animals, which are any isolated and characterized molecules capable of probing the activity/toxicity of the lead compound. Then, the verification of adsorption, distribution, metabolism and excretion (ADME) profile in humans is essential to prove that the potential new AD drugs reaches the central nervous system (CNS), hitting the AD targets.
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- 2017
142. Amyloid β-Peptide 25–35 Self-Assembly and Its Inhibition: A Model Undecapeptide System to Gain Atomistic and Secondary Structure Details of the Alzheimer’s Disease Process and Treatment
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Jessica Fiori, Marco Pistolozzi, Alex F. Drake, Carlo Bertucci, Vincenza Andrisano, Marina Naldi, Rongliang Wu, Angela De Simone, Slawomir Filipek, Krzysztof Mlynarczyk, Naldi M., Fiori J., Pistolozzi M., Drake A.F., Bertucci C., Wu R., Mlynarczyk K., Filipek S., De Simone A., and Andrisano V.
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Models, Molecular ,Circular dichroism ,Curcumin ,ThT fluorescence spectroscopy ,Amyloid ,Physiology ,Stereochemistry ,Cognitive Neuroscience ,Drug design ,Peptide ,In Vitro Techniques ,Biochemistry ,Protein Structure, Secondary ,myricetin ,03 medical and health sciences ,0302 clinical medicine ,Protein structure ,Alzheimer Disease ,Humans ,Protein secondary structure ,030304 developmental biology ,Flavonoids ,chemistry.chemical_classification ,0303 health sciences ,Amyloid beta-Peptides ,Circular Dichroism ,Temperature ,P3 peptide ,amyloid beta-peptide 25-35 ,Cell Biology ,General Medicine ,self-aggregation ,circular dichroism spectroscopy ,curcumin ,(-) tetracycline ,Hydrogen-Ion Concentration ,Tetracycline ,Small molecule ,Peptide Fragments ,Spectrometry, Fluorescence ,chemistry ,030217 neurology & neurosurgery - Abstract
Combined results of theoretical molecular dynamic simulations and in vitro spectroscopic (circular dichroism and fluorescence) studies are presented, providing the atomistic and secondary structure details of the process by which a selected small molecule may destabilize the beta-sheet ordered "amyloid" oligomers formed by the model undecapeptide of amyloid beta-peptide 25-35 [Abeta(25-35)]. Abeta(25-35) was chosen because it is the shortest fragment capable of forming large beta-sheet fibrils and retaining the toxicity of the full length Abeta(1-40/42) peptides. The conformational transition, that leads to the formation of beta-sheet fibrils from soluble unordered structures, was found to depend on the environmental conditions, whereas the presence of myricetin destabilizes the self-assembly and antagonizes this conformational shift. In parallel, we analyzed several molecular dynamics trajectories describing the evolution of five monomer fragments, without inhibitor as well as in the presence of myricetin. Other well-known inhibitors (curcumin and (-)-tetracycline), found to be stronger and weaker Abeta(1-42) aggregation inhibitors, respectively, were also studied. The combined in vitro and theoretical studies of the Abeta(25-35) self-assembly and its inhibition contribute to understanding the mechanism of action of well-known inhibitors and the peptide amino acid residues involved in the interaction leading to a rational drug design of more potent new molecules able to antagonize the self-assembly process
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- 2012
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143. Huprine–Tacrine Heterodimers as Anti-Amyloidogenic Compounds of Potential Interest against Alzheimer’s and Prion Diseases
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Axel Bidon-Chanal, Elisabet Viayna, Miriam Ratia, Carles Galdeano, M. Victòria Clos, Vincenza Andrisano, Cristina Minguillón, Gema C. González-Muñoz, Júlia Relat, Pelayo Camps, Albert Badia, F. Javier Luque, Diego Muñoz-Torrero, Irene Sola, Manuela Bartolini, Francesca Mancini, Xavier Formosa, Mario Salmona, M. Isabel Rodríguez-Franco, Galdeano C., Viayna E., Sola I., Formosa X., Camps P. Badia A., Clos M.V., Relat J., Ratia M., Bartolini M., Mancini F., Andrisano V., Salmona M., Minguillon C., Gonzalez-Munoz G. C., Rodriguez-Franco M. I., Bidon-Chanal A., Luque F. J., and Munoz-Torrero D.
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Models, Molecular ,Molecular model ,Prions ,Peptide ,Heterocyclic Compounds, 4 or More Rings ,AMYLOID BETA-PEPTIDES ,Permeability ,Prion Diseases ,ALZHEIMER DISEASE/DRUG THERAPY ,CHOLINESTERASE INHIBITORS ,Mice ,chemistry.chemical_compound ,Alzheimer Disease ,Drug Discovery ,medicine ,Animals ,Humans ,Structure–activity relationship ,STRUCTURE-ACTIVITY RELATIONSHIP ,Butyrylcholinesterase ,chemistry.chemical_classification ,Brain ,Membranes, Artificial ,Stereoisomerism ,Acetylcholinesterase ,Peptide Fragments ,Recombinant Proteins ,In vitro ,chemistry ,Biochemistry ,Tacrine ,Aminoquinolines ,Molecular Medicine ,PRION DISEASES/*DRUG THERAPY ,Ex vivo ,medicine.drug - Abstract
A family of huprine-tacrine heterodimers has been developed to simultaneously block the active and peripheral sites of acetylcholinesterase (AChE). Their dual site binding for AChE, supported by kinetic and molecular modeling studies, results in a highly potent inhibition of the catalytic activity of human AChE and, more importantly, in the in vitro neutralization of the pathological chaperoning effect of AChE toward the aggregation of both the beta-amyloid peptide (Abeta) and a prion peptide with a key role in the aggregation of the prion protein. Huprine-tacrine heterodimers take on added value in that they display a potent in vitro inhibitory activity toward human butyrylcholinesterase, self-induced Abeta aggregation, and beta-secretase. Finally, they are able to cross the blood-brain barrier, as predicted in an artificial membrane model assay and demonstrated in ex vivo experiments with OF1 mice, reaching their multiple biological targets in the central nervous system. Overall, these compounds are promising lead compounds for the treatment of Alzheimer's and prion diseases.
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- 2012
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144. Immobilized butyrylcholinesterase in the characterization of new inhibitors that could ease Alzheimer’s disease
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Nigel H. Greig, Vincenza Andrisano, Qian-Sheng Yu, Manuela Bartolini, Bartolini M., Greig N.H., Yu Q.S., and Andrisano V.
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Immobilized enzyme ,Drug Evaluation, Preclinical ,Biochemistry ,Article ,Analytical Chemistry ,law.invention ,chemistry.chemical_compound ,ALZHEIMER DISEASE DRUG THERAPY ,Alzheimer Disease ,law ,Humans ,Mode of action ,Chromatography, High Pressure Liquid ,Butyrylcholinesterase ,Cholinesterase ,chemistry.chemical_classification ,IMMOBILIZED ENZYMES ,Chromatography ,biology ,Chemistry ,Organic Chemistry ,HIGH PRESSURE LIQUID CHROMATOGRAPHY ,General Medicine ,Enzymes, Immobilized ,Recombinant Proteins ,Enzyme ,HUMAN BUTYRYLCHOLINESTERASE ,Enzyme inhibitor ,biology.protein ,Recombinant DNA ,Cholinesterase Inhibitors ,Cymserine - Abstract
Focus of this work was the development and characterization of a new immobilized enzyme reactor (IMER) containing human recombinant butyrylcholinesterase (rBChE) for the on-line kinetic characterization of specific, pseudo-irreversible and brain-targeted BChE inhibitors as potential drug candidates for Alzheimer's disease (AD). Specifically, a rBChE-IMER containing 0.99 U of covalently bound target enzyme was purposely developed and inserted into a HPLC system connected to a UV-vis detector. Selected reversible cholinesterase inhibitors, (-)-phenserine and (-)-cymserine analogues, were then kinetically characterized by rBChE-IMER, and by classical in solution assays and their carbamoylation and decarbamoylation constants were determined. The results support the elucidation of the potency, inhibition duration, mode of action and specific structure/activity relations of these agents and allow cross-validation of the two assay techniques.
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- 2009
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145. Novel synthesis of physovenine and physostigmine analogs
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S. Alluri, A. R. White, G. Nikogosyan, Vincenza Andrisano, C.H. Wang, Li-Kang Zhang, C. Monteiro, Manuela Bartolini, G. Mabagos, C. Decarlo, A. K. Ganguly, H. Feng, Wang, C.H., Alluri, S., Nikogosyan, G., Decarlo, C., Monteiro, C., Mabagos, G., Feng, H.H., White, A.R., Bartolini, M., Andrisano, V., Zhang, L.K., and Ganguly, A.K
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Physostigmine ,010405 organic chemistry ,Aché ,Stereochemistry ,Drug Discovery3003 Pharmaceutical Science ,Organic Chemistry ,010402 general chemistry ,01 natural sciences ,Acetylcholinesterase ,Biochemistry ,language.human_language ,Cholinesterase inhibition ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Physovenine ,Drug Discovery ,Physovenine and physostigmine analog ,language ,medicine ,AChE inhibitor ,Radical reaction ,Butyrylcholinesterase ,medicine.drug - Abstract
This Letter describes a versatile synthetic approach to prepare physovenine and physostigmine analogs. A series of analogs were synthesized and evaluated for cholinesterase inhibition activities, including human acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) from human serum.
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- 2016
146. Application of ESI-MS method for detailed characterization of GSK-3β inhibitors by monitoring GSM peptide phosphorylation.Angelini Farmaceutici
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DE SIMONE, ANGELA, NALDI, MARINA, MILELLI, ANDREA, ANDRISANO, VINCENZA, De Simone, A, Naldi, M, Milelli, A, and Andrisano, V
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gsm phosphorylation, gsk-3beta inhibitors, esi-ms - Published
- 2016
147. Application of an ESI-MS method enabling the discovery of new non-ATP competitive GSK-3beta inhibitors
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DE SIMONE, ANGELA, MILELLI, ANDREA, NALDI, MARINA, ANDRISANO, VINCENZA, Angela, De Simone, Andrea, Milelli, Marina, Naldi, Vincenza, Andrisano, De Simone, A, Milelli, A, Naldi, M, and Andrisano, V.
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ESI-MS, nonATP-competitive inhibitors, gsk-3beta ,GSK-3beta, MASS SPECTROMETRY, INHIBITORS CHARACTERIZATION - Published
- 2016
148. Design, Synthesis and Biological profiling of a promising new family of multitarget directed ligands for the treatment of Alzheimer Disease
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Pérez Areales JF, Espergaro A, Sabaté R, Pérez B, Luque FJ, Messeguer A, Munoz Torrero D., BARTOLINI, MANUELA, DE SIMONE, ANGELA, ANDRISANO, VINCENZA, Pérez-Areales JF, Bartolini M, De Simone A, Espergaro A, Sabaté R, Pérez B, Andrisano V, Luque FJ, Messeguer A, and Munoz-Torrero D.
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multitarget agents, AD - Published
- 2016
149. Heterocyclic inhibitors of AChE acylation and peripheral sites
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Maria Laura Bolognesi, Anna Minarini, Vincenza Andrisano, Vincenzo Tumiatti, Michela Rosini, Maurizio Recanatini, Manuela Bartolini, Carlo Melchiorre, Andrea Cavalli, Bolognesi M. L., Andrisano V., Bartolini M., Cavalli A., Minarini A., Recanatini M., Rosini M., Tumiatti V., and Melchiorre C.
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Acylation ,Physostigmine ,Allosteric regulation ,Phenylcarbamates ,Pharmaceutical Science ,Rivastigmine ,Pharmacology ,chemistry.chemical_compound ,Alzheimer Disease ,Heterocyclic Compounds ,Drug Discovery ,Catalytic triad ,medicine ,Humans ,Binding site ,chemistry.chemical_classification ,Binding Sites ,Molecular Structure ,Chemistry ,Acetylcholinesterase ,Enzyme ,Biochemistry ,Cholinergic ,Cholinesterase Inhibitors ,Propidium ,medicine.drug - Abstract
Notwithstanding the criticism to the so called “ cholinergic hypothesis”, the therapeutic strategies for the treatment of Alzheimer's disease (AD) have been mainly centered on the restoration of cholinergic functionality and, until the last year, the only drugs licensed for the management of AD were the acetycholinesterase (AChE) inhibitors. Target enzyme AChE consists of a narrow gorge with two separate ligand binding sites: an acylation site at the bottom of the gorge containing the catalytic triad and a peripheral site located at the gorge rim, which encompasses binding sites for allosteric ligands. The aim of this short review is to update the knowledge on heterocyclic AChE inhibitors able to interact with the two sites of enzymes, structurally related to the well known inhibitors physostigmine, rivastigmine and propidium. The therapeutic potential of the dual site inhibithors in inhibiting amyloid-s aggregatrion and deposition is also briefly summarised.
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- 2005
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150. Cholinesterase Inhibitors: Xanthostigmine Derivatives Blocking the Acetylcholinesterase-Induced β-Amyloid Aggregation
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Lorna Piazzi, Vincenza Andrisano, Piero Valenti, Andrea Cavalli, Alessandra Bisi, Federica Belluti, Angela Rampa, Maurizio Recanatini, Manuela Bartolini, Silvia Gobbi, Belluti F., Rampa A., Piazzi L., Bisi A., Gobbi S., Bartolini M., Andrisano V., Cavalli A., Recanatini M., and Valenti P.
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Models, Molecular ,Carbamate ,Protein Conformation ,Aché ,medicine.medical_treatment ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,medicine ,Moiety ,Cholinesterase ,chemistry.chemical_classification ,Amyloid beta-Peptides ,Binding Sites ,Molecular Structure ,biology ,Chemistry ,Acetylcholinesterase ,language.human_language ,In vitro ,Kinetics ,Enzyme ,Biochemistry ,Enzyme inhibitor ,Butyrylcholinesterase ,language ,biology.protein ,Molecular Medicine ,Carbamates ,Cholinesterase Inhibitors - Abstract
In continuing research that led us to identify a new class of carbamate derivatives acting as potent (Rampa et al. J. Med. Chem. 1998, 41, 3976) and long-lasting (Rampa et al. J. Med. Chem. 2001, 44, 3810) acetylcholinesterase (AChE) inhibitors, we obtained some analogues able to simultaneously block both the catalytic and the beta-amyloid (Abeta) proaggregatory activities of AChE. The key feature of these derivatives is a 2-arylidenebenzocycloalkanone moiety that provides the ability to bind at the AChE peripheral site responsible for promoting the Abeta aggregation. The new carbamates were tested in vitro for the inhibition of both cholinesterases and also for the ability to prevent the AChE-induced Abeta aggregation. All of the compounds had AChE IC(50) values in the nanomolar range and showed the ability to block the AChE-induced Abeta aggregation, thus supporting the feasibility of this new strategy in the search of compounds for the treatment of Alzheimer's disease.
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- 2005
- Full Text
- View/download PDF
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