170,776 research outputs found
Multi-target-directed drugs for neurodegeneration
No full textMULTI-TARGET-DIRECTED DRUGS FOR NEURODEGENERATION
Carlo Melchiorre
Alma Mater Studiorum – University of Bologna, Department of Pharmaceutical Sciences
Via Belmeloro 6, 40126 Bologna, Italy
Drug discovery began as an entirely human-phenotype-based endeavor and, as the understanding of disease pathogenesis advanced, moved to disease models of decreasing complexity (the reductionist approach). From mouse models to protein models via cellular models, these disease models had decreasing relevance for the human condition. As a consequence, drug research has, for decades, been based mainly on a single-target-directed compound strategy; that is, the discovery of a single molecule that is able to modulate the biological profile of a single protein target. This strategy has led to many successful drugs. However, a highly selective ligand for a given target does not always result in a clinically efficacious drug, whether because (a) the ligand does not recognize the target in vivo, (b) the ligand does not reach the site of action, or, (c) the interaction with that particular target is not sufficient enough to efficaciously treat a given disease. Drawbacks a and b can be solved by rationally modifying the ligand. Issue c, however, may not be so easily addressed. This lecture will focus on issue c. In particular, we will consider a new emerging paradigm in drug discovery (‘multi-target-directed ligands’) as a way of potentially overcoming the problems that arise from drugs that hit a single target, drugs that may therefore be inadequate for the treatment of diseases that have multiple pathogenic factors – for example, neurodegenerative diseases
Novel class of quinone-bearing polyamines as multi-target-directed ligands to combat Alzheimer’s disease
No full textMulti-Target-Directed Ligands and Alzheimer’s Disease
Carlo Melchiorre
Dipartimento di Scienze Farmaceutiche, Alma Mater Studiorum – Università di Bologna
Via Belmeloro 6, 40126 Bologna, Italy, [email protected]
Alzheimer’s disease (AD) is a complex neurological affection, characterized by loss of memory and progressive deficits in different cognitive domains and by massive deposits of aggregated proteins that form intracellular tangles and extra-cellular senile plaques. AD still represents a formidable challenge to medicinal chemists because, despite the large amount of basic research carried out into the causes of the disease, progress towards effective pharmacological treatments has been remarkably slow.
The multi-factorial nature of AD forms the basis for the growing consensus that the winning approach for the future treatment of the disease will be therapy with drug cocktails or multi-functional drugs. Clearly, multi-functional drugs would obviate the challenge of administering a combination of drugs with potentially different ADME properties and would also simplify the therapeutic regimen for individuals who may have difficulty with compliance. Consequently, efforts to discover anti-Alzheimer drugs should be devoted to the design of new compounds that are able to hit different selected targets. Following this rationale, new multi-target-directed ligands against AD have been discovered. That is, single molecules that can simultaneously exhibit multiple pharmacological properties, such as cholinergic transmission enhancement and inhibition of both Ab accumulation and oxidative stress, leading to a synergic effect.
The results of this approach will be illustrated
A contribution from Raman spectroscopy for investigations of trans and cis Isomers of Cholesteryl Esters in biological samples
No full textThe cis-trans geometry conversion of double bonds in lipids is an endogenous process that can be mediated by sulfur-centered free radicals [1,2]. Trans isomers of poly-unsaturated fatty acids can be assumed as marker of free radical stress and their recognition in biological samples is a crucial step that can be helped by synthesis and characterization of appropriate reference compounds [3]. Cholesteryl linoleate and arachidonate esters are a fraction of plasma lipids and are interesting targets for their connection with membrane phospholipid turnover and their roles in cardiovascular health. In this context Raman spectroscopy can give a useful contribution, since Raman analysis can be performed directly on the lipid extracts without any derivatization reaction, it is non-destructive, and can rapidly supply some important information. A Raman spectral library of different cis and trans isomers of cholesteryl esters was conveniently generated to be used as references for the examination of complex biological samples and facilitate the isomer recognition. Unsaturated cholesteryl esters having differences in the alkyl chain length and/or the double bonds number, were analysed and characteristic Raman band patterns were identify. In particular, the Raman C=C stretching region (1640-1680 cm-1) provides the most convenient spectral range for evaluating the total unsaturation degree of a sample, as well as information about the presence of trans isomers (Figure 1). In fact, both the ratiometric analysis and the curve fitting procedure in this spectral range gave rise to valuable data in agreement with the gas chromatographic results.
In addition, the potential of Raman analysis for trans isomer detection in biological samples was tested in some plasma cholesteryl ester fractions, whose fatty acid composition was previously estimated by gas chromatography analysis.
References
[1] Chatgilialoglu, C., Ferreri, C., Melchiorre, M., Sansone, A., Torreggiani, A. Chem. Rev. 114 255 (2014)
[2] Torreggiani A, Domènech J, Orihuela R, Ferreri C, Atrian S, Capdevila M, Chatgilialoglu C. Chem Eur J 15 6015 (2009)
[3] Melchiorre, M.; Torreggiani, A.; Chatgilialoglu, C.; Ferreri, C. J. Am. Chem. Soc., 133, 15184 (2011
A rational approach to multi-site-directed ligands for the treatment of Alzheimer’s disease
No full textA RATIONAL APPROACH TO MULTI-SITE-DIRECTED LIGANDS FOR THE TREATMENT OF ALZHEIMER’S DISEASE
Carlo Melchiorre
Department of Pharmaceutical Sciences, Alma Mater Studiorum – University of Bologna, Via Belmeloro 6, 40139 Bologna, Italy
Alzheimer’s disease (AD), the most common cause of dementia, is a complex neurological affection that is characterized by loss of memory and progressive deficits in different cognitive domains and by massive deposits of aggregated proteins to form the intracellular neurofibrillary tangles and the extracellular senile plaques. Even if the primary cause of AD is still speculative, early amyloid-beta peptide (Abeta) aggregates are thought to be mainly responsible for the devastating clinical effects of the disease. Although, at present, the most followed approach to identify AD drugs is the amyloid hypothesis, significant research has been also devoted to the role of free radical formation, oxidative cell damage, and inflammation in the pathogenesis of AD, providing new promising targets and validated animal models. Despite the large amount of basic research carried out into the causes of the disease, AD still represents a formidable challenge to medicinal chemists because progress toward effective pharmacological treatments has been remarkably slow.
The multi-factorial nature of AD forms the basis of the growing consensus that the winning approach for the future treatment of the disease will be the therapy with drugs that are able to hit different selected targets. Following this rationale much effort has been devoted to the discovery of multi-site-directed ligands (MTDLs) against AD, i.e., single molecules that can exhibit multiple pharmacological properties simultaneously, such as cholinergic transmission enhancement and inhibition of Abeta accumulation or oxidative stress, leading to a synergic effect.
To this end, different design strategies in which distinct pharmacophores of different drugs have been combined in the same structure leading to hybrid molecules have been applied. In principle, each pharmacophore of these new drugs should retain the ability to interact with its specific site(s) on the target and consequently to produce specific pharmacological responses that taken together should block or hopefully cure the neurodegenerative process leading to AD.
The results of this approach will be illustrated.
(Supported by grants from the University of Bologna and MIUR.
Potentiation and inhibition ofnicotinic effects on striated muscle by the tetramlne disulfide benextramineB. G. Benfey, L. Brasili, C. Melchiorre, B. Belleau
No full textln low concentratiuns the tetramlne disulfide benextramine potentiated the contracture of the isolated frog rectus abdominus muscle caused by acethilcholine but in presence of physiostigmine or in presence of higher concentration only inhibited the contracture by carbachol or butirrilcholine. The all-carbon analog of benextramine only inhibit the the effect of acetilcholine. The inhibitori effect of benextramine and it all-carbon analog were noncompèotitiveand ready reversible but the potentiating effect of benextramine was not readly reversible
From the universal template strategy to multi-site-directed ligands for the treatment of Alzheimer’s disease
No full textFrom the universal template strategy to multi-site-directed ligands for the treatment of Alzheimer’s disease
Carlo Melchiorre, Department of Pharmaceutical Sciences, Alma Mater Studiorum – University of Bologna, Via Belmeloro 6, 40139 Bologna, Italy
Alzheimer’s disease (AD), the most common cause of dementia, is a complex neurological affection that is characterized by loss of memory and progressive deficits in different cognitive domains and by massive deposits of aggregated proteins to form the intracellular neurofibrillary tangles and the extracellular senile plaques. Even if the primary cause of AD is still speculative, early amyloid-beta peptide (Abeta) aggregates are thought to be mainly responsible for the devastating clinical effects of the disease. Although, at present, the most followed approach to identify AD drugs is the amyloid hypothesis, significant research has been also devoted to the role of free radical formation, oxidative cell damage, and inflammation in the pathogenesis of AD, providing new promising targets and validated animal models. Despite the large amount of basic research carried out into the causes of the disease, AD still represents a formidable challenge to medicinal chemists because progress toward effective pharmacological treatments has been remarkably slow.
The multi-factorial nature of AD forms the basis of the growing consensus that the winning approach for the future treatment of the disease will be the therapy with drugs that are able to hit different selected targets. Following this rationale much effort has been devoted to the discovery of multi-site-directed ligands (MTDLs) against AD, i.e., single molecules that can exhibit multiple pharmacological properties simultaneously, such as cholinergic transmission enhancement and inhibition of Abeta accumulation or oxidative stress, leading to a synergic effect.
To this end, different design strategies in which distinct pharmacophores of different drugs have been combined in the same structure leading to hybrid molecules have been applied. In principle, each pharmacophore of these new drugs should retain the ability to interact with its specific site(s) on the target and consequently to produce specific pharmacological responses that taken together should block or hopefully cure the neurodegenerative process leading to AD.
To design MTDLs for the treatment of AD we have applied the universal template strategy, which foresees that a polyamine backbone may represent a master key (“passe-partout”) in the drug-target recognition process. In other words, a polyamine backbone can be considered a universal template on which suitable groups (pharmacophores) can be mounted to achieve selectivity for any given protein target. This working hypothesis derives from the consideration that the backbone of a protein has only a structural role whereas the lateral chains play a major role in drug-protein target binding through the interaction of aspartate, glutamate, and aromatic residues with cationic ligands by way of a cation-anion or a cation-pi interaction. Considering that proteins may bear several carboxylate and/or aromatic residues somewhere in their structure, in principle, it is possible to design a lead compound having a polyamine backbone which is able to recognize multiple anionic sites of a given protein. Thus, such a ligand may interact with all proteins, provided that the distance separating the amine functions of the ligand fits the distance between the carboxylate or aromatic residues of the protein. An appropriate modification of the chain length separating the nitrogens of a polyamine might give rise to an increase of affinity, whereas the insertion of N-substituents might improve the selectivity as well as the affinity by increasing the overall number of contacts between a drug and a protein. The application of this strategy, leading to the development of Memoquin, will be discussed
MOLECULAR REQUIREMENTS OF THE ACTIVE SITESOF THE CHOLINERGIC RECEPTORSXII (*) - 3-Methyl-2-oxo-L-dimethylaminomethylcyclopentane methiodideas a new selective agonist for the nicotinic receptorM. GIANNELLA, P. ANGELI, C. MELCHIORRE, L. BRASILI
No full textTo investigate further the nature of the active sites olcholinergic reeptors the carbocyclic analogs of isomuscarone and isomuscarine were synthesized- and tested for their cholinergicactivity.Like isomuscarines, such compounds are completely devoid of muscarinic activity which further support the hypothesis that the receptor site,corresponding to position 2 of the ring, cannot accept groups larger than and/or with a dipole having a different direction from that of an etheroxygen.on the other hand nicotinic activity is quite good. In this respectcompound (IV) is particulary interesting, being as actiie as ACh and pratically devoid of muscarinic aciivity
Diastereodivergent organocatalysis for the asymmetric synthesis of chiral annulated furans
No full textDisclosed herein is a stereoselective method for the synthesis of 2,3-furan fused carbocycles bearing adjacent quaternary and tertiary carbon stereocenters. The chemistry is based on an asymmetric addition of β-ketoesters to 2-(1-alkynyl)-2-alkene-1-ones catalysed by natural cinchona alkaloids followed by a silver-catalysed intramolecular cycloisomerisation. By exploiting the distinct catalysis modes of quinine, which can act either as a general base or, upon opportune modifications, as a phase transfer catalyst, a complete switch of the enforced sense of diastereoinduction is achieved. The stereodivergent systems enable access to the full matrix of all possible stereoisomeric products
Direct catalytic enantioselective vinylogous aldol reaction of α-branched enals with isatins
No full textThe direct vinylogous aldol reaction of α-substituted α,β-unsaturated aldehydes with isatins is described. The chemistry provides easy access to valuable 3-substituted 3-hydroxyoxindole derivatives with high stereocontrol and perfect γ-site selectivity. Preliminary mechanistic studies suggest that, depending on the nature of the α-branched enal substituents, two divergent reaction mechanisms can be operating, leading to different products and stereochemical outcomes. © 2012 American Chemical Society
Melchiorre Bega e "Domus"
No full textIl numero di gennaio del 1941 segnò una discontinuità rilevante nella storia della rivista “Domus”, sino ad allora indissolubilmente legata al nome di Gio Ponti, che l’aveva fondata nel 1928 e ne era stato il direttore fino al numero di dicembre del 1940. La direzione, infatti, era stata affidata dall’editore Gianni Mazzocchi a Melchiorre Bega, Giuseppe Pagano e Massimo Bontempelli, un “triunvirato” insolito nel panorama delle riviste d’architettura di quegli anni.
Nell’ambito di uno studio collettivo sull’opera e la figura dell’architetto Bega, basato su ricerche nel suo archivio professionale, acquisito dall’Archivio Progetti dell’Università IUAV di Venezia, il saggio ricostruisce, attraverso l’analisi della pubblicazione e della documentazione conservata nel fondo Bega e in altri archivi, i rapporti di Bega con i condirettori, con i collaboratori e con gli autori più assidui di “Domus”; prende in esame e interpreta criticamente, inoltre, i suoi interessi e il suo contributo alla rivista e, più in generale, al dibattito sull’architettura, il design e l’arte negli anni cruciali e difficili della seconda guerra mondiale
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