1,722,199 research outputs found
Direct, Organocatalytic, Enantioseletcive Michael Reactions: Turning Common Michael Acceptors Into Vinylogous Carbon Nucleophiles
No full textalpha,beta-Unsaturated carbonyl or carbonyl-like moieties are usually envisaged as privileged electrophilic functionalities to be exploited, among others, in Michael addition reactions as well as synchronous or stepwise cycloadditions, opening the way to a wide range of highly valuable beta-functionalized scaffolds. However, behind this common reactivity pattern, an “umpolung” option can be unveiled when an enolizable alkyl group is present at the beta-position of the ylidene. In fact, using a suitable activating catalyst and capitalizing on the vinylogous pro-nucleophilic character of the alkyl group, an addition reaction of these substrates to proper electrophilic acceptors can be fostered to yield olefinic products functionalized at the most distant point of the molecule (C-gamma). We were able to proof this concept on several multidentate scaffolds, namely 3-alkylidene oxindoles,[1] alpha-alkylidene pyrazolinones[2] and dicyano-olefins,[3] by developing direct, organocatalytic, asymmetric, vinylogous Michael addition reactions using nitroolefins or unsaturated aldehydes as electrophilic counterparts. Based on stereocontrolled, covalent or non-covalent dual activation modes, the Cinchona- or prolinol-based organocatalysts performed well, promoting the reactions in high yields and with remarkable control of the regio-, diastereo- and enantioselectivity.
References
1. (a) Curti, C.; Rassu, G.; Zambrano, V.; Pinna, L.; Pelosi, G.; Sartori, A.; Battistini, L.; Zanardi, F.; Casiraghi, G. Angew. Chem. Int. Ed. 2012, 51, 6200. (b) Rassu, G.; Zambrano, V.; Pinna, L.; Curti, C.; Battistini, L.; Sartori, A.; Pelosi, G.; Zanardi, F.; Casiraghi, G. Adv. Synth. Catal. 2013, 355, 1881.
2. Rassu, G.; Zambrano, V.; Pinna, L.; Curti, C.; Battistini, L.; Sartori, A.; Zanardi, F.; Casiraghi, G. Adv. Synth. Catal. 2014, accepted.
3. Dell’Amico, L.; Curti, C.; Zanardi, F. et al. manuscript in preparation
Rokitamycin loaded microparticles based on chitosan for the therapy of amoebic infections.
No full textOBJECTIVES
The aims of this study were: i) to assess the
feasibility of using biodegradable chitosan
microspheres as carriers for controlled release of
rokitamycin (RK), able to improve the antiamoebic
activity of the drug;i ii) to investigate the preparative
parameters for obtaining microspheres based on
chitosan (CH) suitable for ocular or nasal
administration of rokitamycin;ii iii) to verify if it was
possible to maintain microsphere characteristics
suitable for ocular or nasal administration using water
soluble polymers such as new chitosan derivatives,
diethylaminomethyl-(diethyldimethylene ammonium)n
methylchitosans (C7 and C8) or CH salt, chitosan
glutamate (CG);ii iv) to evaluate the influence of
chitosan properties (CH vs CG) on the in vivo
rokitamycin absorption, after nasal administration of
spray dried microspheres.iii
METHODS
Preparation of spray dried microspheres.
Microsphere formulations based on CH or C7 or C8 or
CG were prepared by spray drying (Mini Büchi B-191,
Büchi Laboratoriums-Technik AG, Flawil,
Switzerland) using different drug–polymer ratios (1–3
and 1–4) and starting from feed solutions with diverse
concentrations (1.5%, 1%, 0.5% and 0.25% (w/v)).
Characterisation of Microspheres. Microparticles
prepared were characterised in terms of yield of
production, drug loading and encapsulation efficiency,
particle size, morphology, in vitro drug release, water
uptake, in vitro mucoadhesion, ex vivo drug
permeation, Energy Dispersive X-ray Diffraction
(EDXD) measurements.
Determination of effects of drug and microspheres
on Acanthamoeba growth. Loaded and unloaded CH
microspheres were dispersed in PYG medium and
applied on trophozoite grown in sterile 24-well plates
(Corning). At selected time intervals (3, 4, 7, 9 and 15
days of incubation), amoebas growing in each well
were counted in a Nageotte chamber, using the inverted
microscope.
In vivo RK administration. Nasal administration of
CG and CH microparticles containing RK to each
nostril of the anaesthetized Male Wistar rats was
performed by use of single dose Monopowder P®
insufflators (Valois Dispray). At predetermined times,
blood and liquor samples were collected and analyzed.
Results were compared with those obtained after
intravenous infusion of RK and nasal administration of
RK aqueous suspension.
CONCLUSIONS
The loading of RK into CH microspheres improves
and prolongs the in vitro antiamoebic activity of the
drug.i CH based microspheres with good morphology
and narrow size distribution, able to increase the
dissolution rate of RK, can be obtained by spray drying
using a low concentration of feed solution and 1-4
drug–polymer ratio.ii RK encapsulation into CH
microspheres increases its poor ex vivo permeability
through nasal sheep mucosa. The encapsulation of RK
in C7 and C8 by using the chosen parameters results in
microparticles showing similar or often better
properties than formulations made by CH with respect
to size, in vitro release behaviour and
mucoadhesiveness.ii
Compared with CH particles, CG microspheres
load the drug in amorphous form, leading to the best
improvement of its water solubility. This property, as
well as the rapid water uptake of CG particles,
increases more the release rate of the drug from
microspheres and only after their in vivo nasal
administration, RK goes to the cerebrospinal fluid and
the bloodstream.iii
ACKNOWLEDGEMENTS
This work was supported by MiUR through grant
PRIN05 and Fondazione Banco di Sardegna. The
authors thank “Farmaceutici Formenti S.p.A” and
Valois Pharma for the donation of RK and the powder
insufflators, respectively.
REFERENCES
i Rassu, G., Gavini, E., Mattana, A., Giunchedi, P. Open
Drug Del J, 2, 38-43, 2008.
ii Rassu, G., Gavini, E., Jonassen, H., Zambito, Y., Fogli, S.,
Breschi, MC, Giunchedi, P. J. Pharm. Sci., 98, 4852-4865,
2009.
iii Gavini, E., Rassu, G., Ferraro, L., Generosi, A., Rau, JV.,
Brunetti, A., Giunchedi, P., Dalpiaz, A. J. Pharm. Sci., In
Press
New chitosan derivatives for the preparation of rokitamycin loaded microspheres designed for ocular or nasal administration
No full textAcanthamoeba spp. are the causative agents of granulomatous amoebic encephalitis (GAE) and amoebic keratitis. Recent studies performed by Rassu et al. showed that, compared with the free drug, the loading of rokitamycin in chitosan microspheres improves and prolongs the in vitro antiamoebic activity of rokitamycin. This could be useful in transporting the drug for either ocular application to treat amoebic keratitis or nasal administration as an alternative route for the administration of the drug to the brain in GAE therapy. Starting from the previous study, our goal was to optimize the technological parameters in order to obtain chitosan microparticles loaded with rokitamycin and to evaluate the use of new quaternary ammonium chitosan derivatives in the preparation of spray dried microspheres containing the macrolide; these derivatives showed better characteristics (solubility, penetration enhancement) compared with chitosan itself. Toxicity studies on new polymers were performed. Spray dried loaded microspheres based on chitosan or chitosan derivatives were obtained by using appropriate preparative parameters. Microparticles containing chitosan derivatives showed similar or often better properties than formulations made of chitosan with respect to size, in vitro release behaviour and mucoadhesiveness thus making them more suitable for ocular or nasal administration. New polymers did not demonstrate cytotoxicity
New chitosan derivatives for the preparation of rokitamycin loaded microspheres designed for ocular or nasal administration
No full textAcanthamoeba spp. are the causative agents of granulomatous amoebic encephalitis (GAE) and amoebic keratitis. Recent studies performed by Rassu et al. showed that, compared with the free drug, the loading of rokitamycin in chitosan microspheres improves and prolongs the in vitro antiamoebic activity of rokitamycin. This could be useful in transporting the drug for either ocular application to treat amoebic keratitis or nasal administration as an alternative route for the administration of the drug to the brain in GAE therapy. Starting from the previous study, our goal was to optimize the technological parameters in order to obtain chitosan microparticles loaded with rokitamycin and to evaluate the use of new quaternary ammonium chitosan derivatives in the preparation of spray dried microspheres containing the macrolide; these derivatives showed better characteristics (solubility, penetration enhancement) compared with chitosan itself. Toxicity studies on new polymers were performed. Spray dried loaded microspheres based on chitosan or chitosan derivatives were obtained by using appropriate preparative parameters. Microparticles containing chitosan derivatives showed similar or often better properties than formulations made of chitosan with respect to size, in vitro release behaviour and mucoadhesiveness thus making them more suitable for ocular or nasal administration. New polymers did not demonstrate cytotoxicity
LRRK2 effect on dopamine receptor trafficking: implication in Parkinson’s disease
Full text linkParkinson disease is the second most common neurodegenerative disorder affecting 4 million people worldwide. It is characterized by the loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc) and by the presence of cytoplasmic inclusion bodies (Lewy bodies). Cell death leads to a profound depletion of dopamine neurotransmitter involved mainly in the control of the movement. Mutations in LRRK2 (leucine-rich repeat kinase 2) gene (PARK8; OMIM 609007) are responsible for one of the autosomal-dominant forms of Parkinson’s disease. Up to date, the LRRK2 biological function is largely unknown. LRRK2 has been found in different subcellular districts that play a crucial role in the control of vesicular trafficking: ER, Golgi apparatus and associated vesicles, cytoskeleton, lipid raft and lysosomes. The results of this work indicates that PD-associated mutant G2019S LRRK2 impairs dopamine receptor D1 internalization, leading to an alteration in signal transduction. Moreover, the mutant forms of LRRK2 affect dopamine receptor D2 turnover by decreasing the rate of the receptor trafficking from the Golgi complex to the cell membrane. Collectively, these findings are consistent with the conclusion that LRRK2 influences the motility of neuronal vesicles and the neuronal receptor trafficking
Free thyroid hormone concentration in chronic alcoholes with liver steatosis. M. Langer, S. Rassu, P.P.
No full textSynthesis of D- and L-2-Amino-2-deoxyarabinose and 1,4-Dideoxy-1,4-iminolyxitol by (C2 + C3)-Nitroaldol Addition with 2-O-Benzylglyceraldehyde — Cyclization of N-Protected 1-Amino-4-pentene-2,3-diols to lyxo-Configurated Deoxyimino Sugars (cis-Dihydroxypyrrolidines); Synthesis of Potential Glycosidases Inhibitors — Diastereoselective Conjugate Addition of Ammonia in the Synthesis of Chiral Pyrrolidines.
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