1,720,977 research outputs found
Disegno, sintesi e valutazione farmacologica di nuovi inibitori della proteina Rac1
No full textUna nuova classe di composti efficaci come inibitori dell’interazione RAC1- TIAM è stata progettata e sintetizzata a partire da reagenti semplici ed economici come nitroacetati, tioli, ortoformiato e ciclopentadiene.[1] I composti sintetizzati differiscono per la stereochimica dei sostituenti installati su uno scaffold norbornanico comune. La preparazione dei composti AR129, 148, 177, 180, 194, 201 si basa su un comune schema sintetico che prevede tre step fondamentali: i) costruzione dello scaffold norbornenico mediante reazione di cicloaddizione di Diels-Alder tra l’opportuno acrilato e ciclopentadiene;[2] ii)funzionalizzazione del doppio legame norbornenico mediante idroarilazione di Heck; iii) amminazione di Buchwald seguita da manipolazioni finali di tipo riduttivo e deprotettivo. La procedura è stata ottimizzata ed è stato operato uno scale-up dei composti AR129 e AR 148. Per quanto riguarda la reazione di idroarilazione di Heck è stata osservata una differente reattività dei nuclei norbornenici ottenuti dalla cicloaddizione che ci ha indotto ad approfondire i fattori che regolano regiochimica e reattività di tale reazione su substrate scope più ampio mettendo in evidenza effetti long-range di EWG in posizione endo con l'orbitale p del doppio legame.[3] Successivi sviluppi hanno dimostrato che la reazione procede con successo anche in assenza di leganti di tipo fosfinico. Inoltre la modellazione della reazione sul norbornene semplice ha messo in luce la possibilità di condurre tale reazione anche in solventi non coordinanti rendendo ipotizzabili meccanismi di reazione alternativi.
Riferimenti:
1. N. Ferri, A. Corsini, P. Bottini, F. Clerici, A. Contini, J Med. Chem., 2009, 52(14), 4087 – 90.
2. A. Ruffoni, A. Contini, S. Pellegrino, M. L. Gelmi, R. Soave, F. Clerici, Tetrahedron., 2012, 68, 1951 – 62.
3. A. Ruffoni, A. Casoni, S. Pellegrino, M. L. Gelmi, F. Clerici, Current Organic Chem. 2012, 16, 2
SYNTHESIS OF NEW CONFORMATIONALLY CONSTRAINED BETA-SULFANYL-ALFA- AMINO ACIDS AND THEIR EXPLOITATION IN THE SYNTHESIS OF PEPTIDOMIMETICS
No full textConsidering the great interest in the field of peptidomimetics and the potentiality of the norbornene scaffold, this thesis has been primarily devoted to the synthesis and exploitation a of new class of β-substituted norbornene amino acids as cysteine mimics. The project has been developed with the aim to fill the gap unexpectedly present in the literature in this field and to confirm the unexploited properties of norbornene amino acid as potential building block for peptidomimetics synthesis. At first, we followed the purpose to individuate a novel synthetic strategy to obtain, not only simple but also highly functionalized, norbornene scaffold in grams scale synthesis, in order to make possible further developments in this field and interesting practical applications. Subsequently, we set out to design, realize and conformationally analyze model peptides containing norbornene amino acids in order to demonstrate the ability of such compounds to behave as strong inducers of helical structure and the possibility to be used in the synthesis of unnatural peptides of therapeutic interest. Finally, we explored the field of small molecules as peptidomimetics and demonstrated the advantage of rigid core in the development of new drugs. To do this, we planned to design and realise new chemical entities based on an extensively modified norbornene scaffold which have shown high activity in modulation of Rac1-Tiam1 protein-protein interactions resulting in a new class of potent inhibitors.. During the synthesis of such molecules we also launched a study aiming to better understand which kind of effects a constrained chemical structure, as norbornene scaffold, could have on the regiochemistry in palladium chemistry, imposing a methodic analysis of the steric and electronic effects in the reaction mechanisms
Differenti approcci sintetici di beta-(FENILTIO)-NORBORNAN-2-AMMINOESTERI sostituiti
No full textIn questa comunicazione riportiamo la messa a punto di due diverse strategie per la sintesi 3-(feniltio)-norbornan--amminoesteri sostituiti intermedi chiave per l’ottenimento di molecole ad elevato interesse biologico .
Le due reazioni principali, caratterizzanti tali strategie, consistono in una cicloaddizione di Diels-Alder e una reazione di idroarilazione di Heck. La reazione di cicloaddizione prevede l’utilizzo di 2 diversi dienofili, che, grazie alle loro caratteristiche consentono di orientare la cicloaddizione preferenzialmente verso gli addotti caratterizzati da opposta stereochimica al C-2.
Abbiamo inoltre messo a punto, con ottime rese, una metodica di funzionalizzazione del doppio legame (C-5, C-6) del nucleo norbornenico mediante una reazione di idroarilazione di Heck che prevede l’ utilizzo di acido formico come fonte di nucleofili
Design, synthesis and pharmacological evaluation of new Rac1 protein inhibitors
No full textDesign and Synthesis of a new class of GTPase protein Rac1 inhibitor are described. The entire class called AR were designed based on a crystal structure of the complex Rac1-NS23766. The main features of the synthetic strategy are discussed and permitted the obtainment in satisfactory yield of all the designed compound
Hydroarylation of substituted norbornene amino acids : studies on long-range stereo-electronic effects on the regioselectivity of the addition
No full textStudies on the Pd-catalyzed hydroarylation reaction of a library of differently substituted norbornene amino acid derivatives with numerous halogenoarenes are described. The effect on the regiochemistry of remote substituents, arylating agents and reaction conditions was considered. The reaction occurred with moderate to good yields and a moderate level of regioselectivity being the coupling at C-5 favorite
Short peptides containing Norbornene amino acid (NRB): role of the NRB scaffold in self-assembly
No full textA number of papers report on spontaneous assembly of peptides into ordered nanostructures with a variety of morphologies and this number is still expanding.[1] Besides the numerous advantages of using peptides as building blocks for different types of nanostructures, some limitations are well-known such as a low stability in biological medium and their unstable conformation especially when they are short or medium-sized. The insertion of unnatural amino acids in the peptide sequences is a well-known tool to overcome these problems. Both theoretical and experimental studies on this subject have been published and, in particular, the group of Cα,-tetrasubstituted residues, in which the quaternary α-carbon is part of a ring has been the object of extensive investigation.[2] Notwithstanding this interest, studies on the self-assembly of short peptides containing cyclic Cα-tetrasubstituted amino acids are very rare.[3] The two diastereoisomeric pentapeptides AcAla-NRB-Ala-Aib-AlaNH2 1 and 2, containing the two enantiomers of the non-proteinogenic Cα-tetrasubstituted norbornene amino acid (NRB), were synthesized and their conformational analysis was performed. Interestingly, despite they are made of hydrophobic amino acids, they resulted insoluble in organic solvent, but completely soluble in water. The formation of supramolecular assemblies in water was assessed by TEM and DLS. Moreover, the stability of the aggregates in fetal bovine serum was evaluated and tested by DLS. A comparison between NRB containing peptides and other peptides containing cyclic and non-cyclic Cα-tetrasubstituted residues (i.e. Aib, Ac5AA) was done in order to better understand the role played by the NRB residue in aggregation phenomena
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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