117,786 research outputs found
Malattia di Alzheimer, nuove strategie di Drug Discovery
No full textAlzheimer’s disease (AD) is a complex neurodegenerative disorder resulting from multiple molecular abnormalities, and not from a single target/gene defect. This may explain why the currently available drugs and mostly of the candidates in the pipeline, developed according to the classic drug discovery paradigm of “one-molecule-one-target”, have turned out to be palliative or have failed in achieving any curative effect. This has led to a new paradigm in medicinal chemistry, the “multi-target-directed ligand” design strategy, which has already been exploited at both academic and industrial levels [1]. Multi-target-directed ligands (MTDLs) are small molecules rationally designed to simultaneously modulate multiple targets involved in the neurotoxic cascade. Thus, they should be well-suited to addressing the multifactorial etiopathogenesis of AD.
In parallel, there has been a shift in interest from a target-centric approach, which attempts to limit drug action to the level of individual genes and single proteins, to a system approach, which is better suited to the complexity of the disease. The early signs of this paradigm shift are now being registered, as AD is increasingly studied at multiple levels, and new scientific advances are providing insights into the functioning of interacting biomolecules within cells or organisms [2]. In particular, since a significant number of therapeutic targets reside inside cells and intracellular organelles, subcellular targeting strategies for drug design and delivery now represent a considerable drug discovery challenge [3].
Herein, we present our research efforts that, moving on from classic drug discovery approaches, have produced innovative molecular probes and promising drug candidates for AD treatment.
[1] A. Cavalli, M. L. Bolognesi, A. Minarini, M. Rosini, V. Tumiatti, M. Recanatini, C. Melchiorre. J. Med. Chem. 2008, 51, 347-72.
[2] M. L. Bolognesi, R. Matera, A. Minarini, M. Rosini, V. Tumiatti, C. Melchiorre. Curr. Opin. Chem. Biol. 2009, 13, 303-8.
[3] L. Rajendran, H. J. Knölker, K. Simons. Nature Rev. Drug Discov. 2010, 9, 29-42
AN ENZYMATIC TOOL-BOX FOR LIGNIN OXIDATION/DEGRADATION
No full textLignin is an amorphous polymer characterized by a wide range of molecular mass components, a disordered and branched three-dimensional structure, insoluble in water and in most common solvents. In order to perform lignin degradation, enzymatic treatment could represent an environmentally friendly alternative to chemical methods[1].
The main purpose of this work was to develop an “enzymatic tool-box” for an efficient oxidation and degradation of lignin into aromatic monomers. Biochemical properties of a number of commercial and recombinant ligninolytic oxidative enzymes (laccases, Mn peroxidases and lignin peroxidases) were evaluated under identical experimental conditions, with the final goal to identify interesting biocatalysts for lignin degradation[2]. The effect of pH, temperature, NaCl, DMSO and Tween-80 on the enzymatic activity has been investigated. The activity of novel enzymes, such as the membrane-bound polyphenol oxidase from the marine bacterium Marinomonas mediterranea[3] and a peroxidase produced by Nonomuraea gerenzanensis, was also evaluated[4].
A new high-throughput colorimetric screening to assay the oxidation/degradation of lignin by different enzymes was developed: this method facilitates the identification of optimal conditions for a lignin treatment based on the combined use of various laccases and peroxidases[5]. On this side, coupling the colorimetric assay with a size-exclusion chromatography analysis allows to identify changes in lignin molecular mass distribution due to enzymatic treatment. Notably, the enzymatic tool-box also comprises etherases, cathecol oxidase and demethylase activities. Finally, a chemo-enzymatic process to depolymerise lignin was carried out on lignin linkage model compounds and technical lignins.
Altogether, the combination of chemical and enzymatic approaches could represent an innovative and feasible way for valorisation of lignin under mild conditions.
This work was done as part of Biorefill (ID42611813) and ValorPlus (no FP7-KBBE-2013-7-613802) projects.
[1] Pollegioni, L.; Tonin, F.; Rosini, E. FEBS Journal 2015, 282(7), 1190-1213.
[2] Tonin, F.; Melis, R.; Cordes, A.; Sanchez-Amat, A.; Pollegioni, L.; Rosini, E. New Biotechnology 2016,
33(3), 387-398.
[3] Tonin, F.; Rosini, E.; Piubelli, L.; Sanchez-Amat, A.; Pollegioni, L. Protein Expression and Purification
2016, (123), 60-69.
[4] Casciello, C.; Tonin, F.; Berini, F.; Fasoli, E.; Marinelli, F.; Pollegioni, L.; Rosini, E. Biotechnology Re- ports 2017, (13), 49-57.
[5] Tonin, F.; Vignali, E.; Pollegioni, L.; D’Arrigo, P.; Rosini, E. Enzyme and Microbial Technology 2017,
(96), 143-150
Sintesi formale della fragranza muschiata macrociclica (12R)-12-metil-9-ossa-14-tetradecanolide tramite catalisi asimmetrica
No full textSINTESI FORMALE DELLA FRAGRANZA MUSCHIATA MACROCICLICA
(12R)-12-METIL-9-OSSA-14-TETRADECANOLIDE, TRAMITE CATALISI ASIMMETRICA
Patrizia Scafato, Lidia Marino, Carlo Rosini
Dipartimento di Chimica, Università degli Studi della Basilicata, via N. Sauro 85, 85100 Potenza
[email protected]
Le fragranze muschiate sono ingredienti fondamentali per l’industria profumiera1, tra queste una delle più potenti è l’(R)-12-metil-9-ossa-14-tetradecanolide 1. In particolare, il lattone 1 è interessante in quanto è il primo esempio di fragranza muschiata in cui l’enantiomero (R), è profumato e presenta uno dei più bassi limiti di percezione olfattiva (0.09 ng/L) mentre l’enantiomero (S) è inodore2. In letteratura è riportata la sintesi di (R)-1 basata sulla desimmetrizzazione asimmetrica dell’anidride 3-metil-glutarica che, impiegando quantità stechiometriche di reagente chirale, fornisce in otto passaggi il composto 1 con un e.e dell’87% e una resa totale del 2%.2
In questa comunicazione proponiamo una nuova via d’accesso alla porzione chirale 2 di tale fragranza il cui passaggio enantioselettivo consiste nell’addizione coniugata asimmetrica catalitica di Me2Zn al 5,6-diidro-2H-piran-2-one commerciale. Tale addizione, seguita da apertura in situ dell’enolato ottenuto, ha fornito, in un unico passaggio e con 84% di e.e, l’idrossiestere 3. Da quest’ultimo è stato ottenuto l’alcol monoprotetto 2 con tre passaggi sintetici rispetto ai quattro riportati in letteratura, un eccesso enantiomerico paragonabile e soprattutto utilizzando quantità catalitiche di reagente chirale.
1. a) Kraft, P.; Bajgrowicz, J.A.; Denis, C.; Fráter, G. Angew. Chem. Int. Ed. 2000, 39, 2980; b) Brenna, E.; Fuganti, C.; Serra, S. Tetrahedron:Asymmetry, 2003, 14, 1.
2. Kraft, P.; Cadalbert Synthesis, 1998, 1662.
Lavoro eseguito con il supporto finanziario del MIUR-COFIN 2004: “Aromi e fragranze
L' Idilliade sacra. Sacri idillij di d. Celso Lesuarte Rosini, can reg. Later. negl'Animosi il Raffermato. De' principali misterij della vita di N. Signore ...
No full textImpronta: u-o- n-e- ueto SiSi (3) 1621 (A)I singoli idilli con front. propri
Breaking lignin: blue and yellow laccases for a green chemistry
No full textLignin is an amorphous polymer with a molecular mass around 10 kDa that presents a three-dimensional structure disordered and branched, insoluble in water and most common solvents. During the industrial processes, lignin must be degraded and effectively removed. Enzymatic hydrolysis could be an environmentally friendly alternative to chemical methods to perform lignin degradation. The identification of enzymes able to efficiently fragmenting lignin, i.e., an "enzymatic tool box", is of utmost importance. On this side, laccase represents an enzymatic class of main relevance.
Laccases are attracting great scientific interest because of their very basic requirements and huge catalytic capabilities: this renders it one of the ‘‘greenest’’ enzymes [1].
In order to identify interesting lignin degrading biocatalysts, in this study we evaluated the main biochemical properties of a number of commercial and recombinant laccases under identical experimental conditions. The kinetic properties of laccases has been determined on 3 substrates: ABTS, catechol and 2,6-dimethoxyphenol (2,6-DMP). The microbial Bacillus licheniformis laccase (BALL) showed the highest specific activity and catalytic efficiency on ABTS, while the recombinant OB1 from Basidiomycete PM-1 showed the highest affinity for this compound [2]. The stability on pH, temperature, detergents and DMSO of the different laccases was also assessed.
Finally, a change in MW distribution after incubation of lignin with the laccase from Trametes versicolor was observed in gel permeation chromatography.
This work was done as part of the ValorPlus project that has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no FP7-KBBE-2013-7-613802.
[1] L. Pollegioni, F. Tonin, E. Rosini, FEBS J. 282 (7) (2015) 1190-1213
[2] F. Tonin, R. Melis, A. Cordes, A. Sanchez-Amat, L. Pollegioni, E. Rosini, Submitte
Tropos ligand for the asymmetric addition of phenylboronic acid to enones
No full textTROPOS LIGAND FOR THE ASYMMETRIC ADDITION OF PHENYLBORONIC ACID TO ENONES
P. Scafato, F. Caprioli, L. Pisani, C. Rosini
Dipartimento di Chimica, Università degli Studi della Basilicata, via N. Sauro, 85; Potenza.
e-mail: [email protected]
The asymmetric conjugate addition of arylboronic acids to activated olefins is nowadays an efficient method for the stereoselective construction of C(sp2)-C(sp3) bonds, given the large spectrum of substrates which can be used and the availability of many different chiral ligands.1 In this context, phosphoramidites certainly constitute a class of versatile and easily tunable ligands.2
We report herein the asymmetric addition of phenylboronic acid to different cycloalkenones with both the tropos phosphoramidite (S)-L1 and the non tropos (S)-L2 ligand. Different enantioselectivities have been obtained, mainly depending on the ring size of the substrates, with (S)-L1 affording higher e.e. values than (S)-L2. These results can been explained reasoning that, only for the tropos phosphoramidite, a “chiral pocket” is formed when the ligand links to the metal atom.
References:
1) (a) Fagnou, K.; Lautens, M. Chem. Rev. 2003, 103, 169-196; (b) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829-2844.
2) a) Boiteau, J.-M.; Imbos, R.; Minnaard, A. J.; Feringa, B. L. Org. Lett. 2003, 5, 681-684.
3) P. Scafato, G. Cunsolo, S. Labano, C. Rosini, Tetrahedron 2004, 60, 8801-8806
Reactive oxygen species as a double-edged sword: The role of oxidative enzymes in antitumor therapy
No full textA number of approaches have been developed over the years to manage cancer, such as chemotherapy using low-molecular-mass molecules and radiotherapy. Here, enzymes can also find useful applications. Among them, oxidases have attracted attention because of their ability to produce reactive oxygen species (ROS, especially hydrogen peroxide) in tumors and potentially modulate the production of this cytotoxic compound when enzymes active on substrates present in low amounts are used, such as the d-amino acid oxidase and d-amino acid couple system. These treatments have been also developed for additional cancer treatment approaches, such as phototherapy, nutrient starvation, and metal-induced hydroxyl radical production. In addition, to improve tumor specificity and decrease undesired side effects, oxidases have been targeted by means of nanotechnologies and protein engineering (i.e., by designing chimeric proteins able to accumulate in the tumor). The most recent advances obtained by using six different oxidases (i.e., the FAD-containing enzymes glucose oxidase, d- and l-amino acid oxidases, cholesterol oxidase and xanthine oxidase, and the copper-containing amine oxidase) have been reported. Anticancer therapy based on oxidase-based ROS production has now reached maturity and can be applied in the clinic
Sintesi stereoselettive di (R)-12-metiltridecanolide e (S)-muscolide fragranze a struttura macrociclica tramite la sequenza addizione coniugata asimmetrica/ ossidazione di Baeyer –Villiger
No full textSINTESI STEREOSELETTIVE DI (R)-12-METILTRIDECANOLIDE E (S)-MUSCOLIDE FRAGRANZE A STRUTTURA MACROCICLICA TRAMITE LA SEQUENZA ADDIZIONE CONIUGATA ASIMMETRICA/OSSIDAZIONE DI BAEYER-VILLIGER
P. Scafato, A. Larocca, C. Rosini
Dipartimento di Chimica, Università degli Studi della Basilicata, via N. Sauro 85, 85100 Potenza
[email protected]
La fragranze muschiate sono di fondamentale importanza commerciale poichè costituiscono spesso le note di fondo di un profumo. Negli ultimi anni quelle a struttura macrociclica (chetoni e lattoni) sono state oggetto di grande attenzione rappresentando un’ importante alternativa alle note fragranze sintetiche a struttura benzenoide, sia per la loro intensa profumazione che per la loro migliore biodegradabilità.1
In questa comunicazione riportiamo la sintesi dei lattoni macrociclici 1 e 2, presenti entrambi nell’olio essenziale estratto dalle radici dell’Angelica Officinalis, i quali possiedono un odore muschiato molto gradevole e persistente. Lo schema sintetico da noi elaborato prevede l’ossidazione di Baeyer-Villiger dell’(R)-3-metilciclotridecanone e dell’(S)-3-metilciclopentadecanone rispettivamente, ottenibili tramite addizione coniugata asimmetrica di dimetilzinco ai corrispondenti chetoni ,-insaturi, a loro volta sintetizzati a partire da opportuni chetoni macrociclici commerciali e a basso costo. Nella reazione di addizione coniugata di dimetilzinco al 2-ciclotridecenone abbiamo utilizzato, come induttore chirale, il fosforammidito (R)-32 ottenendo l’(R)-3-metilciclotridecanone con 70% di resa e 86% ee. Risultati simili (68% di resa e 84% ee) si sono ottenuti nell’addizione di dimetilzinco al 2-ciclopentadecenone effettuata in presenza del legante (S)-3. Per quanto riguarda, invece, la reazione di Baeyer-Villiger sui chetoni otticamente attivi, essa ha permesso di ottenere, in buone rese, i lattoni con rapporti regioisomerici (70:30 nel caso di 1 e 80:20 per 2) a favore dei prodotti da noi desiderati.
I risultati ottenuti indicano che la sequenza addizione coniugata asimmetrica/ossidazione di Baeyer-Villiger costituisce un’efficiente ed economica via d’accesso a fragranze muschiate otticamente attive aventi struttura macrociclica e di alto valore commerciale.
1. a) Kraft, P.; Bajgrowicz, J.A.; Denis, C.; Frater, G. Angew. Chem. Int. Ed. 2000, 39, 2980; b) Brenna, E.; Fuganti, C.; Serra, S. Tetrahedron:Asymmetry, 2003, 14, 1; c) Fehr, C.; Galindo, J.; Farris, I.; Cuenca, A. Helv. Chem. Acta, 2004, 87, 1737.
2. Scafato, P.; Cunsolo, G.; Labano, S.; Rosini, C. Tetrahedron, 2004, 60, 8801.
Lavoro eseguito con il supporto finanziario del MIUR-COFIN 2004: “Aromi e fragranze
Sintesi stereoselettive di lattoni macrociclici componenti dell’olio essenziale delle radici dell’ Angelica officinalis
No full textSINTESI STEREOSELETTIVA DI LATTONI MACROCICLICI COMPONENTI DELL’OLIO ESSENZIALE DELLE RADICI DELL’ANGELICA OFFICINALIS
Alessandra D’Elia, Augusto Larocca, Patrizia Scafato, Carlo Rosini
Dipartimento di Chimica, Università degli Studi della Basilicata, via N. Sauro 85, 85100
Potenza
[email protected]
I lattoni macrociclici (R)-12-metil-13-tridecanolide 1 e (S)-muscolide 2 sono costituenti naturali dell’Angelica Officinalis e conferiscono all’olio essenziale che si estrae dalle radici di questa pianta una gradevole profumazione muschiata. Al contrario i corrispondenti enantiomeri, (S)-1 ed (R)-2 hanno un odore canforaceo non molto piacevole.1 In questa comunicazione riportiamo la sintesi stereoselettiva di tali fragranze naturali, (R)-1 e (S)-2. Lo schema sintetico da noi elaborato prevede l’ossidazione di Baeyer-Villiger dell’(R)-3-metilciclotridecanone e dell’(S)-3-metilciclopentadecanone rispettivamente, ottenibili tramite addizione coniugata asimmetrica catalitica di Me2Zn ai corrispondenti chetoni ,-insaturi,2 a loro volta sintetizzati a partire da opportuni chetoni macrociclici commerciali e a basso costo. La reazione di addizione coniugata di dimetilzinco al 2-ciclotridecenone ha fornito l’(R)-3-metilciclotridecanone con 70% di resa e 92% ee. Risultati simili (68% di resa e 84% ee) si sono ottenuti nell’addizione di dimetilzinco al 2-ciclopentadecenone. La reazione di Baeyer-Villiger sui chetoni otticamente attivi ha, infine, permesso di ottenere, in buone rese (80-86%), i lattoni con rapporti regioisomerici (70:30 nel caso di 1 e 80:20 per 2) a favore dei prodotti da noi desiderati.
1. a) Bollbuck, P; Kraft, P.; Tochtermann, W Tetrahedron, 1998, 54, 7633; b) Brenna, E.; Fuganti, C.; Serra, S. Tetrahedron:Asymmetry, 2003, 14, 1.
2. Scafato, P.; Cunsolo, G.; Labano, S.; Rosini, C. Tetrahedron, 2004, 60, 8801.
Lavoro eseguito con il supporto finanziario del MIUR-COFIN 2004: “Aromi e fragranze
Asymmetric conjugate addition of arylboronic acids to enones mediated by rhodium/phosphoramidite complex
No full textAsymmetric conjugate addition of arylboronic acids to enones mediated by rhodium/phosphoramidite complex
Patrizia Scafato, Francesca Caprioli, Carlo Rosini
Dipartimento di Chimica, Università degli Studi della Basilicata, via N. Sauro, 85; Potenza. [email protected]
The asymmetric rhodium-catalyzed conjugate addition of aryl boronic acids nowadays is the method of choice for the stereoselective introduction of an aryl group in the β position of activated olefins.1
The catalytic efficiency of phosphoramidite L* has been tested on such a reaction with different enones, providing high yields and enantioselectivities (up to 96% e.e.) dependent on the nature of the carbonyl compound. Furthermore, preliminary investigations on the asymmetric addition of phenylboronic acid to chromones, substrates never utilized for this reaction, are reported. The results obtained indicate that also this reaction can occur with high enantioselectivity. Moreover, this synthetic approach could represent a new convenient access to chiral flavanones,2 an important class of natural and synthetic products which possess an impressive and varied array of biological and pharmacological properties.
1. (a) Fagnou, K.; Lautens, M. Chem. Rev. 2003, 103, 169-196; (b) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829-2844; (c) Christoffers, J.; Koripelly, G.; Rosiak, A.; Rössle, M. Synthesis 2007, 1279-1300. 2. Moorty, N. S. H. N.; Singh, R. J.; Sing, H. P.; Gupta, S. D. Chem. Pharm. Bull. 2006, 54, 1384-1390
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