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1.
2.
Mater Today Bio ; 24: 100935, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38239894
3.
Chem Sci ; 11(44): 12009-12020, 2020 Oct 05.
Article in English | MEDLINE | ID: mdl-34123216

ABSTRACT

Enzymes acting over glyceryl ethers are scarce in living cells, and consequently biocatalytic transformations of these molecules are rare despite their interest for industrial chemistry. In this work, we have engineered and immobilised a glycerol dehydrogenase from Bacillus stearothermophilus (BsGlyDH) to accept a battery of alkyl/aryl glyceryl monoethers and catalyse their enantioselective oxidation to yield the corresponding 3-alkoxy/aryloxy-1-hydroxyacetones. QM/MM computational studies decipher the key role of D123 in the oxidation catalytic mechanism, and reveal that this enzyme is highly enantioselective towards S-isomers (ee > 99%). Through structure-guided site-selective mutagenesis, we find that the mutation L252A sculpts the active site to accommodate a productive configuration of 3-monoalkyl glycerols. This mutation enhances the k cat 163-fold towards 3-ethoxypropan-1,2-diol, resulting in a specific activity similar to the one found for the wild-type towards glycerol. Furthermore, we immobilised the L252A variant to intensify the process, demonstrating the reusability and increasing the operational stability of the resulting heterogeneous biocatalyst. Finally, we manage to integrate this immobilised enzyme into a one-pot chemoenzymatic process to convert glycidol and ethanol into 3-ethoxy-1-hydroxyacetone and (R)-3-ethoxypropan-1,2-diol, without affecting the oxidation activity. These results thus expand the uses of engineered glycerol dehydrogenases in applied biocatalysis for the kinetic resolution of glycerol ethers and the manufacturing of substituted hydroxyacetones.

4.
Graefes Arch Clin Exp Ophthalmol ; 256(3): 535-546, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29353344

ABSTRACT

PURPOSE: To study the safety and biocompatibility of Laponite clay (LAP) within an intravitreal and suprachoroidal administration in rabbit eyes. METHODS: Thirty-two New Zealand albino rabbits were divided into two experimental groups to test intravitreal (IVT group) and suprachoroidal (SCS group) administration of a 100-µl and 50-µl Laponite suspension respectively. Following injection, the eyes were monitored by ocular tonometry, slit-lamp eye examination and indirect ophthalmoscopy, at 24 h, 1, 4, 12, and 14 weeks post administration. Histological examination was also performed to determine whether any ocular pathological change had occurred. Throughout the study, LAP presence in vitreous was estimated by complexometric titration with ethylenediaminetetraacetic acid (EDTA), taking advantage of the Laponite high content of magnesium ions. RESULTS: Neither significant differences in the intraocular pressure, nor relevant ocular complications were found in the two experimental groups after LAP administration. The histology of the retina remained unchanged. LAP presence in vitreous could be indirectly confirmed by complexometric titration until 14 weeks post administration in eyes of IVT group. CONCLUSION: Laponite could be considered as a vehicle for potential clinical use in ocular drug administration, due to its proven ocular biocompatibility and its transparency in gel state.


Subject(s)
Retina/pathology , Retinal Diseases/drug therapy , Silicates/administration & dosage , Vision, Ocular , Aluminum Silicates/administration & dosage , Animals , Biocompatible Materials/administration & dosage , Clay , Disease Models, Animal , Electroretinography , Female , Intravitreal Injections , Ophthalmoscopy , Rabbits , Retina/drug effects , Retina/physiopathology , Retinal Diseases/diagnosis , Retinal Diseases/physiopathology
5.
Phys Chem Chem Phys ; 19(41): 28302-28312, 2017 Oct 25.
Article in English | MEDLINE | ID: mdl-29034391

ABSTRACT

In this work we report the preparation of mixtures of several alkyl glyceryl ethers, as hydrogen bond donor compounds, with two ammonium salts, choline chloride and N,N,N-triethyl-2,3-dihydroxypropan-1-aminium chloride. The stability of the mixtures at different molar ratios and temperatures has been evaluated in order to determine the formation of low melting mixtures. Liquid and stable mixtures have been characterized and their physico-chemical properties such as density, viscosity, refractive index, conductivity and surface tension have been measured in the temperature range of 293.15 K to 343.15 K. Comparison of the mixtures prepared herein with the ones containing glycerol and choline chloride evidences the possibility of tuning the physico-chemical properties by changing the substitution pattern in the hydrogen bond donor compound or in the ammonium salt, thus broadening the scope of application of these mixtures.

6.
Curr Eye Res ; 42(2): 244-251, 2017 02.
Article in English | MEDLINE | ID: mdl-27400236

ABSTRACT

PURPOSE: To develop a simple, specific, and rapid method to determine corticosteroid concentrations in vitreous humor. METHODS: An analytical method based on high-pressure liquid chromatography-tandem mass spectrometry (HPLC-MS) with a simple extraction procedure was developed. New Zealand albino rabbits (n = 54) received a single (0.1 mL) intravitreal injection of dexamethasone (DXM, 0.1 mg), methylprednisolone (MP, 2 mg), or triamcinolone acetonide (TA, 10 mg). Eyes were enucleated and mean vitreous steroid levels were quantified at 12 h and 1, 2, 3, 7, and 14 days. RESULTS: Corticosteroids were extracted from the vitreous with acetonitrile, and TA was extracted with ethyl acetate, yielding high protein precipitation and clean solution samples. Vitreous samples were analyzed by isocratic HPLC-MS with mobile phase comprising acetonitrile and 2 mM ammonium formate buffer in water, pH 3.5. The linear range was 50-100,000 ng/g with a lower quantification limit of 45 ng/g for DXM and MP, and 50 ng/g for TA. Vitreous levels of DXM and MP were not detectable 14 days post-administration. Vitreous levels of TA were positive and stable throughout the study in both injected and control eyes. CONCLUSIONS: The HPLC-MS analytical method is an alternative to HPLC-MS/MS methods, sensitive enough for identifying and quantifying steroids in vitreous humor at a therapeutic dosage scale.


Subject(s)
Chromatography, High Pressure Liquid/methods , Dexamethasone/pharmacokinetics , Methylprednisolone/pharmacokinetics , Retinal Diseases/drug therapy , Tandem Mass Spectrometry/methods , Triamcinolone Acetonide/pharmacokinetics , Vitreous Body/metabolism , Animals , Dexamethasone/administration & dosage , Disease Models, Animal , Female , Glucocorticoids/metabolism , Glucocorticoids/pharmacokinetics , Intravitreal Injections , Methylprednisolone/administration & dosage , Rabbits , Retinal Diseases/diagnosis , Retinal Diseases/metabolism , Triamcinolone Acetonide/administration & dosage
7.
Eur J Pharm Biopharm ; 108: 83-90, 2016 Nov.
Article in English | MEDLINE | ID: mdl-27594212

ABSTRACT

Laponite clay is able to retain dexamethasone by simple physisorption, presumably accomplished by hydrogen bonding formation and/or complexation with sodium counterions, as shown by solid state NMR. The physisorption can be somehow modulated by changing the solvent in the adsorption process. This simple system is able to deliver dexamethasone in a controlled manner to solutions used as models for vitreous humor. The proven biocompatibility of laponite as well as its transparency in the gel state, together with the simplicity of the preparation method, makes this system suitable for future in vivo tests of ophthalmic treatment.


Subject(s)
Dexamethasone/chemistry , Drug Carriers/chemistry , Silicates/chemistry , Vitreous Body/metabolism , Adsorption , Aluminum Silicates , Biocompatible Materials/chemistry , Clay , Dexamethasone/administration & dosage , Drug Delivery Systems , Humans , Hydrogen Bonding , Magnetic Resonance Spectroscopy , Molecular Structure , Sodium/chemistry , Solvents/chemistry , Spectrophotometry, Infrared , Static Electricity
8.
Org Biomol Chem ; 13(35): 9314-22, 2015 Sep 21.
Article in English | MEDLINE | ID: mdl-26240011

ABSTRACT

Several kinds of polytopic chiral ligands (including ditopic, tritopic and tetratopic), based on the bis(oxazoline) and azabis(oxazoline) motifs, have been tested in the preparation of recoverable catalytic systems for the Henry reaction. The results obtained with the different ligands are, in general, good, but they point to the existence of a delicate balance between the coordinating ability of the ligand, the catalytic activity and the recovery of the catalyst by formation of the coordination polymer, related to the easiness to form oligomeric species in solution.

9.
Org Biomol Chem ; 11(26): 4327-32, 2013 Jul 14.
Article in English | MEDLINE | ID: mdl-23657431

ABSTRACT

The purely inorganic copper oxide on silica catalyzes the reaction of methyl phenyldiazoacetate with N-methyl indole under mild reaction conditions, giving the alkylation (formally a C-H insertion) in position 3, and the catalyst can be recovered and reused at least in 5 consecutive runs with only minor loss in activity. The scope of the reaction includes various diazo compounds and indole or pyrrole derivatives leading to alkylation or cyclopropanation depending on the heterocycle structure. An alternative mechanism, without reduction of Cu(II) to Cu(I), is proposed on the basis of the obtained results.


Subject(s)
Copper/chemistry , Indoles/chemistry , Silicon Dioxide/chemistry , Alkylation , Catalysis , Diazonium Compounds/chemistry
10.
J Org Chem ; 78(12): 5851-7, 2013 Jun 21.
Article in English | MEDLINE | ID: mdl-23701290

ABSTRACT

The combination of chiral preparative HPLC separation, VCD measurements, and theoretical calculations allows the unambiguous determination of the absolute configuration of the conformationally flexible products of copper-catalyzed carbene insertion reactions. DFT calculations were used to predict the stereochemical outcome of the copper-bis(oxazoline)-catalyzed C-H insertion reaction between methyl diazophenylacetate and tetrahydrofuran and also to predict the absolute configuration of the major stereoisomers derived from the same reaction with different cyclic ethers. These predictions were verified experimentally through NMR and VCD spectroscopy and allowed rationalization of the stereochemical outcome of these reactions without further derivatization of the products, which can be prblematic under certain conditions as described herein.

11.
Langmuir ; 28(31): 11364-75, 2012 Aug 07.
Article in English | MEDLINE | ID: mdl-22775393

ABSTRACT

Solid-state NMR experiments show that the behavior of supported 1-butyl-3-methylimidazolium hexafluorophosphate ionic liquid phases depends on the type of support and the phase thickness. A mobile nearly liquid phase is obtained on silica, on the basis of the line widths of the bands in (1)H, (31)P, and (13)C spectra. However, the mobility is somehow restricted, as shown by the possibility of using the cross-polarization technique, although with slow dynamics. On laponite clay, a layered material with a negatively charged surface, a truly solid phase is obtained at low coverage, whereas the increase in ionic liquid loading leads to a second liquid phase, as shown by the presence of two contributions with very different line widths. These two phases seem to coexist without exchange in the NMR time frame. Heteronuclear correlation experiments evidence different relative dispositions of the imidazolium-surface-PF(6) system, with only aromatic protons involved in all the interactions on silica but participation of the benzylic groups (N-CH(3) and/or N-CH(2)) in the case of laponite clay.

12.
J Org Chem ; 77(13): 5525-32, 2012 Jul 06.
Article in English | MEDLINE | ID: mdl-22667829

ABSTRACT

An efficient release-capture strategy for the recovery and reuse of enantioselective catalysts in the Henry reaction is described. This strategy is based on the precipitation of an insoluble coordination polymer at the end of each reaction, allowing easy separation from products. The coordination polymer is formed through aggregation of Cu(II) ions with ditopic bisoxazoline-based chiral ligands. Up to 11 catalytic cycles have been conducted keeping good yields and enantioselectivities.


Subject(s)
Aldehydes/chemistry , Nitro Compounds/chemical synthesis , Organometallic Compounds/chemistry , Oxazoles/chemistry , Polymers/chemistry , Catalysis , Copper/chemistry , Ligands , Molecular Structure , Nitro Compounds/chemistry , Organometallic Compounds/chemical synthesis , Polymers/chemical synthesis , Stereoisomerism
13.
Dalton Trans ; 41(27): 8285-9, 2012 Jul 21.
Article in English | MEDLINE | ID: mdl-22643457

ABSTRACT

Recoverable multiphase enantioselective catalytic systems for the Kharasch-Sosnovsky oxidation of cycloalkenes with tert-butyl peroxybenzoate are described, based on the use of [BMIM][PF(6)] and a new solvent derived from glycerol as the catalyst reservoir phases, and chiral copper complexes with different ligands from the bis(oxazoline) family. The best results are obtained with the glycerol-derived solvent and a recently described azabisoxazoline-based ditopic ligand, allowing up to four uses of the catalytic phase with good results.

14.
Org Biomol Chem ; 9(17): 6075-81, 2011 Sep 07.
Article in English | MEDLINE | ID: mdl-21750830

ABSTRACT

The efficiency of chiral bis(oxazoline)- and azabis(oxazoline)-copper complexes in the enantioselective carbene insertion into C-H bonds of cyclic ethers in homogeneous phase strongly depends on the structure of the substrate. The immobilization on laponite clay by electrostatic interactions not only allows the recovery and reuse of the heterogeneous catalysts, but in some cases also improves enantioselectivity and overall chemoselectivity, making possible reactions that do not take place or lead to low yields in solution, even with the commonly used Rh(2)[S-DOSP](4) catalyst.

16.
Chemistry ; 17(2): 529-39, 2011 Jan 10.
Article in English | MEDLINE | ID: mdl-21207570

ABSTRACT

An extensive computational study has been carried out on different catalytic systems for cyclopropanation reactions based on copper. Most DFT schemes used present drawbacks that preclude the calculation of accurate absolute kinetic properties (energy barriers) of such systems, excepting the M05 and M06 suites of density functionals. On the other hand, there is a wide range of DFT methods capable of reproducing relative energy values, which can be easily translated into selectivities. Most of the theoretical levels used tend to overestimate activation barriers, allowing the location of the transition state (TS) on the potential-energy surface (PES) of the most reactive systems, which are probably artifacts of the method. However, after a thorough analysis of the calculated PES, and the origin of the energy differences obtained for the different alkene approaches in chiral systems, it is found that energy differences are almost constant over a wide range of geometries covering the reaction channel zone in which the true TS on the Gibbs free-energy surface (GFES) lies. Therefore, many computational schemes can still be used confidently to explain and predict enantioselectivities in these systems.

17.
Dalton Trans ; 39(8): 2098-107, 2010 Feb 28.
Article in English | MEDLINE | ID: mdl-20148230

ABSTRACT

Aza-pyridinoxazoline ligands, a new class of C(1)-symmetric ligands, are described and tested in the heterogeneous enantioselective catalysis of a cyclopropanation reaction, with the aim of improving surface confinement effects by the clay support on the reaction stereoselectivity. In the case of trans/cis diastereoselectivity, these surface effects lead to a systematic reversal of selectivity, cis-cyclopropanes being favored. Regarding the enantioselectivities, support confinement has a positive effect in the case of major cis-cyclopropane products, leading to moderate enantioselectivity values (60% ee). A theoretical (DFT) mechanistic study is carried out to explain the origin of the enantioselectivity in the homogeneous phase at a molecular level, and to get insights on the geometries of the key intermediates and transition structures.

19.
Chem Soc Rev ; 38(3): 695-706, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19322463

ABSTRACT

In this tutorial review, we discuss how recycling and stability advantages alone are frequently not sufficient to justify the effort necessary to immobilize chiral complexes unless additional advantages are found. Nanostructured solids with well-controlled surfaces and pores may act as nanoreactors, hindering or even blocking some of the reaction channels, and hence modifying the stereochemical result of the reaction. The use of support effects to improve or change the enantioselectivity is emerging as an interesting field, whose understanding might allow, in the near future, the design of chiral ligands better adapted to this strategy.

20.
Chem Rev ; 109(2): 360-417, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19090693
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