Publications by authors named "Federica Balzano"

47 Publications

A Proline Mimetic for the Design of New Stable Secondary Structures: Solvent-Dependent Amide Bond Isomerization of ()-Indoline-2-carboxylic Acid Derivatives.

J Org Chem 2021 06 3;86(12):7946-7954. Epub 2021 Jun 3.

Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Via G. Moruzzi 13, 56124 Pisa, Italy.

A thorough experimental and computational study on the conformational properties of ()-indoline-2-carboxylic acid derivatives has been conducted. Methyl ()-1-acetylindoline-2-carboxylate, both a mimetic of proline and phenylalanine, shows a remarkable tendency toward the amide isomer when dissolved in polar solvents. This behavior is opposite to the general preference of proline for the isomer, making indoline-2-carboxylic acid a good candidate for the design of different secondary structures and new materials.
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http://dx.doi.org/10.1021/acs.joc.1c00184DOI Listing
June 2021

A Dimeric Thiourea CSA for the Enantiodiscrimination of Amino Acid Derivatives by NMR Spectroscopy.

J Org Chem 2021 06 21;86(11):7381-7389. Epub 2021 May 21.

Department of Chemistry and Industrial Chemistry, University of Pisa, via Moruzzi 13, 56124 Pisa, Italy.

The reaction of benzoyl isothiocyanate with (1,2)-1,2-bis(2-hydroxyphenyl)ethylenediamine afforded a new thiourea chiral solvating agent (CSA) with a very high ability to differentiate H and C NMR signals of simple amino acid derivatives, even at low concentrations. The enantiodiscrimination efficiency was higher with respect to that of the parent monomer, a thiourea derivative of 2-((1)-1-aminoethyl)phenol, thus putting into light the relevance of the cooperativity between the two molecular portions of the dimer in a cleft conformation stabilized by interchain hydrogen bond interactions. An achiral base additive (DABCO or DMAP) played an active role in the chiral discrimination processes, mediating the interaction between the CSA and the enantiomeric mixtures. The chiral discrimination mechanism was investigated by NMR spectroscopy through the determination of complexation stoichiometries, association constants, and the stereochemistry of the diastereomeric solvates.
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http://dx.doi.org/10.1021/acs.joc.1c00340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279476PMC
June 2021

Lopinavir/ritonavir, a new galenic oral formulation from commercial solid form, fine-tuned by nuclear magnetic resonance spectroscopy.

Eur J Hosp Pharm 2020 Nov 19. Epub 2020 Nov 19.

Chemistry and Industrial Chemistry Department, University of Pisa, Pisa, Italy.

Objectives: The lopinavir/ritonavir combination is one of the first antiretroviral drugs to be used in the treatment of COVID-19. In incapacitated patients, such as those in intensive care, an oral liquid formulation is needed. In Italy a marketed formulation is available, but only by importing it from other European countries. A galenic oral formulation prepared in the hospital pharmacy from lopinavir/ritonavir tablets was fine-tuned, evaluating the content of the active pharmaceutical ingredient (API) and stability of the formulation by using nuclear magnetic resonance (NMR) spectroscopy.

Methods: To overcome the insolubility of lopinavir/ritonavir in water, ethanol and glycerol have been used as additional excipients. To define the best excipient proportion and best preparation method, three different formulations (ethanol 7.1-7.5%, glycerol 6-15%, and water) and two different preparation procedures (two step vs one step) have been studied. Each formulation has been compared with Kaletra oral solution (lopinavir 80 mg/mL, ritonavir 20 mg/mL) by NMR spectroscopy. API content and stability were measured.

Results: The presence of ethanol and glycerol as co-solvents is crucial both to improve solubilisation and promote the stability of the oral form. In the two-step preparation method, when crushed tablets were first dispersed in the ethanol/glycerol mixture and then in water, the content of solubilised active ingredients was equal or only slightly lower than the standard Kaletra (range 89-100%). The one-step method provided a comparable API content (65%) to that obtained by using water as the sole dispersing medium.

Conclusions: The two-step setup method with final 7.1% ethanol and 11% glycerol concentration is an efficient procedure for extemporaneous preparation of lopinavir/ritonavir liquid formulations from crushed tablets. The method combines simplicity of preparation and reconstitution in the hospital ward with good solubilisation, comparable to the commercial solution, and stability of active ingredients over time.
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http://dx.doi.org/10.1136/ejhpharm-2020-002389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677895PMC
November 2020

2-Methyl-β-cyclodextrin grafted ammonium chitosan: synergistic effects of cyclodextrin host and polymer backbone in the interaction with amphiphilic prednisolone phosphate salt as revealed by NMR spectroscopy.

Int J Pharm 2020 Sep 28;587:119698. Epub 2020 Jul 28.

Department of Chemistry and Industrial Chemistry, University of Pisa, via Moruzzi 13, 56124 Pisa, Italy. Electronic address:

Reduced molecular weight chitosan was quaternized with 2-chloro-N,N-diethylethylamine to obtain a water soluble derivative (N-rCh). Methylated-β-cyclodextrin (MCD), with 0.5 molar substitution, was covalently linked to N-rCh through 1,6-hexamethylene diisocyanate spacer to give the derivatized ammonium chitosan N-rCh-MCD. To shed light on the role of the cyclodextrin pendant in guiding binding interactions with amphiphilic active ingredients, corticosteroid prednisolone phosphate salt (PN) was considered. The deep inclusion of PN into cyclodextrin in PN/MCD model system was pointed out by analysis of H NMR complexation shifts, 1D ROESY spectra, and diffusion measurements (DOSY). By using proton selective relaxation rates measurements as investigation tool, the superior affinity of N-rCh-MCD towards PN was demonstrated in comparison with parent ammonium chitosan N-rCh.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119698DOI Listing
September 2020

Thiourea Derivative of 2-[(1)-1-Aminoethyl]phenol: A Flexible Pocket-like Chiral Solvating Agent (CSA) for the Enantiodifferentiation of Amino Acid Derivatives by NMR Spectroscopy.

J Org Chem 2020 04 30;85(8):5342-5350. Epub 2020 Mar 30.

Department of Chemistry and Industrial Chemistry, University of Pisa, via Moruzzi 13, 56124 Pisa, Italy.

Thiourea derivatives of 2-[(1)-1-aminoethyl]phenol, (1,2)-1-amino-2,3-dihydro-1-inden-2-ol, (1,2)-(1,2)-1-amino-2,3-dihydro-1-inden-2-ol, and ()-1-phenylethanamine have been compared as chiral solvating agents (CSAs) for the enantiodiscrimination of derivatized amino acids using nuclear magnetic resonance (NMR) spectroscopy. Thiourea derivative, prepared by reacting 2-[(1)-1-aminoethyl]phenol with benzoyl isothiocyanate, constitutes an effective CSA for the enantiodiscrimination of 3,5-dinitrobenzoyl (DNB) derivatives of amino acids with free or derivatized carboxyl functions. A base additive 1,4-diazabicyclo[2.2.2]octane(DABCO)/,-dimethylpyridin-4-amine (DMAP)/NBuOH) is required both to solubilize amino acid derivatives with free carboxyl groups in CDCl and to mediate their interaction with the chiral auxiliary to attain efficient differentiation of the NMR signals of enantiomeric substrates. For ternary systems CSA/substrate/DABCO, the chiral discrimination mechanism has been ascertained through the NMR determination of complexation stoichiometry, association constants, and stereochemical features of the diastereomeric solvates.
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http://dx.doi.org/10.1021/acs.joc.0c00027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997569PMC
April 2020

Improvement of Peptide Affinity and Stability by Complexing to Cyclodextrin-Grafted Ammonium Chitosan.

Polymers (Basel) 2020 Feb 19;12(2). Epub 2020 Feb 19.

Department of Pharmacy, University of Pisa, via Bonanno Pisano 6, 56126 Pisa, Italy.

Cyclodextrin-grafted polymers are attractive biomaterials that could bring together the host-guest complexing capability of pristine cyclodextrin and the pharmaceutical features of the polymeric backbone. The present paper is aimed at characterizing the potential application of ammonium-chitosan grafted with 2-methyl-β-cyclodextrin (N-rCh-MCD) as the functional macromolecular complexing agent for the oral administration of the neuropeptide dalargin (DAL). Specific NMR characterization procedures, along with UV and fluorescence techniques, as well as biological in vitro assessments have been performed. The results indicate that N-rCh-MCD forms water-soluble complexes with DAL, with a prevalent involvement of Tyr or Phe over Leu and Ala residues. The association constant of DAL with the polymeric derivative is one order of magnitude higher than that with the pristine cyclodextrin (K: 2600 M and 120 M, respectively). Additionally, N-rCh-MCD shields DAL from enzymatic degradation in gastrointestinal in vitro models with a three-fold time delay, suggesting a future pharmaceutical exploitation of the polymeric derivative. Therefore, the greater affinity of N-rCh-MCD for DAL and its protective effect against enzymatic hydrolysis can be attributed to the synergistic cooperation between cyclodextrin and the polymer, which is realized only when the former is covalently linked to the latter.
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http://dx.doi.org/10.3390/polym12020474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077720PMC
February 2020

Binding and mucoadhesion of sulfurated derivatives of quaternary ammonium-chitosans and their nanoaggregates: An NMR investigation.

J Pharm Biomed Anal 2020 Jan 30;177:112852. Epub 2019 Aug 30.

Department of Chemistry and Industrial Chemistry, University of Pisa, via Moruzzi 13, 56124 Pisa, Italy. Electronic address:

The effect of insertion of SH and S-protected groups on the binding and mucoadhesion properties of quaternary ammonium-chitosans and their nanoparticulate forms has been investigated by NMR spectroscopy. Diclofenac sodium salt has been assumed as low molecular weight probe to detect the different binding behaviour of polymeric materials; mucin from bovine submaxillary glands was selected as the model protein for differentiating their mucoadhesion. NMR proton selective relaxation rates of the probe molecule were remarkably sensitive to the presence of very low amounts of sulfurated moieties. Impact of supramolecular aggregation in nanostructured species was demonstrated as well as the relevance of S-protection.
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http://dx.doi.org/10.1016/j.jpba.2019.112852DOI Listing
January 2020

Impact of mucoadhesive polymeric nanoparticulate systems on oral bioavailability of a macromolecular model drug.

Eur J Pharm Biopharm 2018 Sep 10;130:281-289. Epub 2018 Jul 10.

Department of Pharmacy, University of Pisa, Via Bonanno 33, 56126 Pisa, Italy. Electronic address:

Nanoparticles (NP) only different in mucoadhesivity are compared for impact on drug oral bioavailability. Two polymeric NP types based on quaternary ammonium-chitosan (NP QA-Ch) and S-protected thiolated derivative thereof (NP QA-Ch-S-pro), respectively, containing the macromolecular drug model, FD4, were prepared by crosslinking each polymer with reduced MW hyaluronic acid. The structure of basic polymers was determined by HNMR analysis. NP were similar in size (371 ± 38 vs. 376 ± 82 nm); polydispersity index (0.39 ± 0.08 vs. 0.41 ± 0.10); zeta potential (13.4 ± 0.9 vs. 11.9 ± 1.2 mV); reversible interactions with drug (bound drug, 67 vs. 66%); encapsulation efficiency (23 ± 5 vs. 23 ± 8%); release properties (15% released in 15 h in both cases); and apparent permeation across excised rat intestine (P, 8.8 ± 0.8 vs. 10 ± 1 cm/s). Then the differences in NP transport ratio through mucus (TR, 0.75 vs. 0.37) and adhesion to excised rat intestinal mucosa (adsorbed fraction, 23 ± 3 vs. 45 ± 2%) were ascribed to higher mucoadhesivity of NP QA-Ch-S-pro compared to NP QA-Ch. This directly influenced drug oral bioavailability in rats (T, 1 vs. 2 h; AUC, 1.7 ± 0.3 vs. 2.9 ± 0.4 μg/mL min, for NP QA-Ch and NP QA-Ch-S-pro, respectively). Mucoadhesivity increases drug bioavailability by retaining NP at its absorption site and opposing its transit down the GI tract. Data on drug accumulation in rat liver allows the assertion that NP is absorbed by transcytosis across intestinal epithelium and transported from blood into liver by Kuppfer cells.
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http://dx.doi.org/10.1016/j.ejpb.2018.07.010DOI Listing
September 2018

Connecting the solution chemistry of PbI and MAI: a cyclodextrin-based supramolecular approach to the formation of hybrid halide perovskites.

Chem Sci 2018 Mar 12;9(12):3200-3208. Epub 2018 Feb 12.

Istituto di Nanotecnologia CNR-Nanotec , Distretto Tecnologico via Arnesano 16 , 73100 Lecce , Italy . Email: ; Email:

The evolution from solvated precursors to hybrid halide perovskite films dictates most of the photophysical and optoelectronic properties of the final polycrystalline material. Specifically, the complex equilibria and the importantly different solubilities of lead iodide (PbI) and methylammonium iodide (MAI) induce inhomogeneous crystal growth, often leading to a defect dense film showing non-optimal optoelectronic properties and intrinsic instability. Here, we explore a supramolecular approach based on the use of cyclodextrins (CDs) to modify the underlying solution chemistry. The peculiar phenomenon demonstrated is a tunable complexation between different CDs and MA cations concurrent to an out of cage PbI intercalation, representing the first report of a connection between the solvation equilibria of the two perovskite precursors. The optimal conditions in terms of CD cavity size and polarity translate to a neat enhancement of PbI solubility in the reaction media, leading to an equilibration of the availability of the precursors in solution. The macroscopic result of this is an improved nucleation process, leading to a perovskite material with higher crystallinity, better optical properties and improved moisture resistance. Remarkably, the use of CDs presents a great potential for a wide range of device-related applications, as well as for the development of tailored composite materials.
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http://dx.doi.org/10.1039/c7sc05095jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916222PMC
March 2018

A water-soluble, mucoadhesive quaternary ammonium chitosan-methyl-β-cyclodextrin conjugate forming inclusion complexes with dexamethasone.

J Mater Sci Mater Med 2018 Mar 30;29(4):42. Epub 2018 Mar 30.

Department of Pharmacy, University of Pisa, via Bonanno 33, 56126, Pisa, Italy.

The ocular bioavailability of lipophilic drugs, such as dexamethasone, depends on both drug water solubility and mucoadhesion/permeation. Cyclodextrins and chitosan are frequently employed to either improve drug solubility or prolong drug contact onto mucosae, respectively. Although the covalent conjugation of cyclodextrin and chitosan brings to mucoadhesive drug complexes, their water solubility is restricted to acidic pHs. This paper describes a straightforward grafting of methyl-β-cyclodextrin (MCD) on quaternary ammonium chitosan (QA-Ch60), mediated by hexamethylene diisocyanate. The resulting product is a water-soluble chitosan derivative, having a 10-atom long spacer between the quaternized chitosan and the cyclodextrin. The derivative is capable of complexing the model drug dexamethasone and stable complexes were also observed for the lyophilized products. Furthermore, the conjugate preserves the mucoadhesive properties typical of quaternized chitosan and its safety as solubilizing excipient for ophthalmic applications was preliminary assessed by in vitro cytotoxicity evaluations. Taken as a whole, the observed features appear promising for future processing of the developed product into 3D solid forms, such as controlled drug delivery systems, films or drug eluting medical devices.
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http://dx.doi.org/10.1007/s10856-018-6048-2DOI Listing
March 2018

Cyclodextrins as inhibitors of the precipitation of riboflavin-5'-phosphate due to presence of zinc chloride: A NMR investigation.

J Pharm Biomed Anal 2017 Sep 31;144:183-187. Epub 2016 Dec 31.

Dipartimento di Chimica e Chimica Industriale, Università degli Studi di Pisa, via G. Moruzzi 13, 56124 Pisa, Italy.

Several cyclodextrins (CDs) were probed in order to counteract the precipitation of riboflavin-5'-phosphate (or flavin mononucleotide, FMN-P) due to the presence of divalent cations, by exploiting Nuclear Magnetic Resonance (NMR) spectroscopy both for quantitative analyses and stereochemical characterizations. Among CDs, β-cyclodextrin (β-CD) showed the best solubilizing power in virtue of the formation of a 1-2 FMN-P/β-CD complex, the stereochemistry of which was ascertained by ROESY (Rotating-frame Overhauser Enhanced SpectroscopY) measurements.
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http://dx.doi.org/10.1016/j.jpba.2016.12.039DOI Listing
September 2017

Role of nanostructured aggregation of chitosan derivatives on [5-methionine]enkephalin affinity.

Carbohydr Polym 2017 Feb 29;157:321-324. Epub 2016 Sep 29.

Università di Pisa, Dipartimento di Chimica e Chimica Industriale, Via Giuseppe Moruzzi 13, 56124 Pisa, Italy. Electronic address:

Affinities of quaternary ammonium-chitosan conjugates, their thiolated derivatives and corresponding nanostructured aggregates towards the hydrophilic drug [5-methionine]enkephalin were compared by Nuclear Magnetic Resonance (NMR) spectroscopic methods based on proton selective relaxation rate measurements. Nanoaggregates showed enhanced drug affinity in comparison with corresponding polymers, especially in the case of thiolated systems.
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http://dx.doi.org/10.1016/j.carbpol.2016.09.089DOI Listing
February 2017

Molecularly imprinted cyclodextrin nanosponges for the controlled delivery of L-DOPA: perspectives for the treatment of Parkinson's disease.

Expert Opin Drug Deliv 2016 Dec 24;13(12):1671-1680. Epub 2016 Oct 24.

a Dipartimento di Chimica , University of Torino , Torino , Italy.

Background: L-DOPA is an amino acid precursor to the neurotransmitter dopamine that is extensively used as a prodrug for the treatment of Parkinson's disease. However, L-DOPA is an unstable compound: when exposed to light or added to aqueous solutions, it may degrade, compromising its therapeutic properties.

Methods: In this work, a new type of drug-loaded cyclodextrin-based nanosponge, obtained using molecular imprinting, is described for the prolonged and controlled release of L-DOPA. The molecularly imprinted nanosponges (MIP-NSs) were synthesized by cross-linking β-cyclodextrin with 1,1'-carbonyldiimidazole in DMF in the presence of L-DOPA as a template molecule. TGA, DSC and FTIR analyses were performed to characterize the interactions between L-DOPA and the two nanosponge structures. Quantitative NMR spectroscopy was used to determine the amount and the affinity of L-DOPA entrapped in the nanosponges. The in vitro L-DOPA release kinetics from the NSs were quantitatively determined by HPLC analysis.

Results: The MIP-NSs show a slower and more prolonged release profile than the non-imprinted nanosponges. No degradation of the L-DOPA hosted in the MIP-NSs was observed after long-term storage at room temperature.

Conclusions: The MIP-NSs are a promising alternative for the storage and controlled delivery of L-DOPA.
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http://dx.doi.org/10.1080/17425247.2017.1248398DOI Listing
December 2016

Multiscale morphology design of hybrid halide perovskites through a polymeric template.

Nanoscale 2015 Dec 29;7(45):18956-63. Epub 2015 Oct 29.

Dipartimento di Matematica e Fisica "E. De Giorgi", Universita' del Salento, Via per Arnesano, 73100 Lecce, Italy.

Hybrid halide perovskites have emerged as promising active constituents of next generation solution processable optoelectronic devices. During their assembling process, perovskite components undergo very complex dynamic equilibria starting in solution and progressing throughout film formation. Finding a methodology to control and affect these equilibria, responsible for the unique morphological diversity observed in perovskite films, constitutes a fundamental step towards a reproducible material processability. Here we propose the exploitation of polymer matrices as cooperative assembling components of novel perovskite CH3NH3PbI3 : polymer composites, in which the control of the chemical interactions in solution allows a predictable tuning of the final film morphology. We reveal that the nature of the interactions between perovskite precursors and polymer functional groups, probed by Nuclear Magnetic Resonance (NMR) spectroscopy and Dynamic Light Scattering (DLS) techniques, allows the control of aggregates in solution whose characteristics are strictly maintained in the solid film, and permits the formation of nanostructures that are inaccessible to conventional perovskite depositions. These results demonstrate how the fundamental chemistry of perovskite precursors in solution has a paramount influence on controlling and monitoring the final morphology of CH3NH3PbI3 (MAPbI3) thin films, foreseeing the possibility of designing perovskite : polymer composites targeting diverse optoelectronic applications.
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http://dx.doi.org/10.1039/c5nr04715cDOI Listing
December 2015

Monomeric and dimeric 9-O anthraquinone and phenanthryl derivatives of cinchona alkaloids as chiral solvating agents for the NMR enantiodiscrimination of chiral hemiesters.

Chirality 2015 Oct 11;27(10):693-9. Epub 2015 Aug 11.

Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Pisa, Italy.

Mono- and bis-alkaloid chiral auxiliaries with anthraquinone or phenanthryl cores were probed as chiral solvating agents (CSAs) for the enantiodiscrimination of chiral cyclic hemiesters. The dimeric anthraquinone derivative and the monomeric phenanthryl one showed remarkable efficiency in the nuclear magnetic resonance (NMR) differentiation of enantiomeric mixtures of hemiesters. An anthraquinone analogous with a single alkaloid unit was remarkably less effective. The conformational prevalence of the chiral auxiliaries were ascertained by NMR.
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http://dx.doi.org/10.1002/chir.22488DOI Listing
October 2015

Stability of hydrophilic vitamins mixtures in the presence of electrolytes and trace elements for parenteral nutrition: a nuclear magnetic resonance spectroscopy investigation.

J Pharm Biomed Anal 2015 Mar 17;107:7-10. Epub 2014 Dec 17.

U.O. Farmaceutica - Gestione del farmaco, Azienda Ospedaliero Universitaria Pisana, via Roma 67, 56126 Pisa, Italy.

In total parenteral nutrition (TPN), especially in the case of preterm infants, simultaneous administration of vitamins and trace elements is still a problematic issue: guidelines put in evidence the lack of specific documentation. In this work NMR spectroscopy was applied to the study of vitamins (pyridoxine hydrochloride, thiamine nitrate, riboflavin-5'-phosphate and nicotinamide) stability in presence of salts and trace elements. Vitamins in D2O were first analyzed by (1)H NMR spectroscopy in absence of salts and trace elements; changes in chemical shifts or in diffusion coefficients, measured by NMR DOSY technique, were analyzed. The effects of salts and trace elements on single vitamins and on their admixtures were then investigated by performing quantitative analyses during 48h. Selected vitamins are subject to intermolecular interactions. No degradative effects were observed in presence of salts and trace elements. Only riboflavin-5'-phosphate is subject to precipitation in presence of divalent cations; however, at low concentration and in presence of other vitamins this effect was not observed. Solutions analyzed, in the condition of this study, are stable for at least 48h and vitamins and trace elements can be administered together in TPN.
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http://dx.doi.org/10.1016/j.jpba.2014.12.008DOI Listing
March 2015

Hydrolytic inhibition of α-chymotrypsin by 2,8,14,20-tetrakis(D-leucyl-D-valinamido)resorc[4]arenecarboxylic acid: a spectroscopic NMR and computational combined approach.

Org Biomol Chem 2015 Jan;13(3):916-24

Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Via G. Moruzzi 3, 56124 Pisa, Italy.

The stereochemical features of 2,8,14,20-tetrakis(D-leucyl-D-valinamido)resorc[4]arenecarboxylic acid and the N-succinyl-L-alanyl-L-alanyl-L-prolyl-L-phenylalanine-4-nitroanilide polypeptide substrate were investigated by nuclear magnetic resonance spectroscopy. Proton selective relaxation parameters gave the basis for the inhibitory activity of resorcin[4]arene in the hydrolysis of the polypeptide substrate by α-chymotrypsin. Results showed that an interaction between the resorcin[4]arene and α-chymotrypsin does occur, and involves the hydrophobic moiety of the macrocycle. This interaction is further reinforced by polar groups located on the side chains of the resorcin[4]arene, whereas the macrocycle-polypeptide substrate interaction is negligible. Conformational analysis and interaction studies carried out by molecular modeling are in good agreement with the NMR data, thus providing an additional support to the rationalization of the inhibitory potential of resorcin[4]arenes on the α-chymotrypsin activity.
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http://dx.doi.org/10.1039/c4ob01936aDOI Listing
January 2015

Synergistic effects of trace amounts of water in the enantiodiscrimination processes by lipodex E: a spectroscopic and computational investigation.

Chirality 2015 Feb 20;27(2):95-103. Epub 2014 Oct 20.

Department of Chemistry and Industrial Chemistry, University of Pisa, Pisa, Italy.

Nuclear magnetic resonance (NMR) investigations on mixtures containing octakis(3-O-butanoyl-2,6-di-O-pentyl)-γ-cyclodextrin (Lipodex E) and each enantiomer of methyl-2-chloropropionate (MCP) ascertained the role of trace amounts of water in the enantiodiscrimination processes. Water is deeply included into the cyclodextrin and favors the formation of the inclusion complex with (S)-MCP, whereas (R)-MCP is only slightly affected, thus causing a significant increase of NMR differentiation. Molecular dynamics simulations were performed to shed light on the possible behavior of Lipodex E in different conditions (i.e., solvent, inclusion complexes), providing energetic and atomistic details that are in agreement with NMR observations.
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http://dx.doi.org/10.1002/chir.22394DOI Listing
February 2015

Mucoadhesivity and release properties of quaternary ammonium-chitosan conjugates and their nanoparticulate supramolecular aggregates: an NMR investigation.

Int J Pharm 2014 Jan 22;461(1-2):489-94. Epub 2013 Dec 22.

Dipartimento di Farmacia, Università degli Studi di Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy.

Selective relaxation rate measurements effectively proved the affinity of dexamethasone 21-phosphate disodium salt for quaternary ammonium-chitosan conjugates, their thiolated derivatives and the corresponding nanostructured aggregates. Affinity was also probed by dynamic dialysis. The release profile of dexamethasone loaded nanoparticles was defined by quantitative NMR and interrupted dialysis experiments, and mucoadhesivity of empty nanoparticles was effectively probed by selective relaxation rate measurements.
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http://dx.doi.org/10.1016/j.ijpharm.2013.12.018DOI Listing
January 2014

Enantiopure cis-2,5-disubstituted 2,5-dihydropyrroles from D-glycal-derived vinyl aziridines.

Org Lett 2013 Dec 14;15(23):6026-9. Epub 2013 Nov 14.

Dipartimento di Farmacia, Via Bonanno 33 and Dipartimento di Chimica e Chimica Industriale, via Risorgimento 35, Università di Pisa , 56126 Pisa, Italy.

Upon treatment with the K- and Li-enolates of a methylene active compound, such as dimethyl malonate and dibenzoylmethane, D-allal- and D-galactal-derived vinyl N-mesyl aziridines are stereoselectively transformed, in a unique step, into diastereoisomeric, highly functionalized, enantiopure cis-2,5-disubstituted N-mesyl-2,5-dihydropyrroles.
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http://dx.doi.org/10.1021/ol402927sDOI Listing
December 2013

Stereochemical preference of 2'-deoxycytidine for chiral bis(diamido)-bridged basket resorcin[4]arenes.

Chirality 2013 Dec 28;25(12):840-51. Epub 2013 Aug 28.

Dipartimento di Chimica e Tecnologie del Farmaco, Università di Roma "La Sapienza", Roma, Italy.

Bis(diamido)-bridged basket resorcin[4]arene (all-S)-1 and its (all-R)-1 enantiomer proved able to interact with 2'-deoxycytidine (2) and pyrimidine nucleoside analogs in dimethyl sulfoxide (DMSO) solution. In such a solvent, the resorcinarene hosts adopt a preferential 1,3-alternate-like conformation, with a larger cavity delimited by two syn 3,5-dimethoxyphenyl moieties, and two external pockets, each delimited by the other 3,5-dimethoxyphenyl group and its diamido arm (the wing). Complexation phenomena were investigated by nuclear magnetic resonance (NMR) methods, including (1)H NMR DOSY and 1D ROESY experiments, and molecular modeling. Heteroassociation constants of [(all-S)-1·2] and [(all-R)-1·2] diastereoisomeric complexes were obtained from diffusion data by single point measurements, and from nonlinear fitting of 1H NMR chemical shifts. Selective proton relaxation rate measurements allowed us to significantly discriminate the two complexes by identifying two different interaction sites of the guest in the resorcin[4]arene host, depending on its configuration.
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http://dx.doi.org/10.1002/chir.22224DOI Listing
December 2013

Chiral NMR solvating additives for differentiation of enantiomers.

Top Curr Chem 2013 ;341:69-131

Dipartimento di Chimica e Chimica Industriale, Università di Pisa, via Risorgimento 35, 56126, Pisa, Italy,

This chapter will describe the general features and main categories of chiral solvating agents (CSAs) for NMR spectroscopy, spanning from low-medium sized CSAs to macrocyclic ones. CSAs based on chiral ionic liquids (CILs) will be introduced in view of their increasing popularity, and, finally, a short paragraph will be dedicated to special applications of CSAs in particular experimental conditions. Several valuable works, which are mainly devoted to investigate enantiodifferentiation mechanisms by NMR, will not be discussed. The main objective is to identify the current trend in the research areas dedicated to the development of new CSAs for NMR spectroscopy.
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http://dx.doi.org/10.1007/128_2013_445DOI Listing
May 2014

Mucoadhesive properties of tamarind-seed polysaccharide/hyaluronic acid mixtures: A nuclear magnetic resonance spectroscopy investigation.

Carbohydr Polym 2013 Jan 25;91(2):568-72. Epub 2012 Aug 25.

Dipartimento di Chimica e Chimica Industriale, Università degli Studi di Pisa, Via Risorgimento 35, I-56126 Pisa, Italy.

Mixtures of tamarind-seed polysaccharide (TSP) and hyaluronic acid (HA), which are employed as artificial tears for ophthalmic applications in the eye dry syndrome, were investigated by NMR spectroscopy by analyzing the effect of TSP/HA ratio and total concentration on their capability to form stable aggregates with enhanced mucoadhesive properties over those of the separate polysaccharides. The effect of TSP, HA or TSP/HA mixtures on the affinity of diclofenac sodium salt (DS) to mucin (BSM) was ascertained by means of proton selective relaxation rate measurements and assumed as the basis to compare polysaccharides mucoadhesive properties. The NMR relaxation parameters of pure DS (2mM), binary DS/BSM (5mg/mL or 10mg/mL) and ternary DS/BSM/polysaccharide systems (polysaccharide=TSP, HA or variable ratios TSP/HA mixtures) were compared in aqueous medium. The experimental data demonstrate that the minimum concentration of 1.5mg/mL of each polysaccharide is needed to have formation of a stable TSP/HA aggregate endowed with NMR detectable mucoadhesive properties and inside which reciprocal synergistic interaction occurs.
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http://dx.doi.org/10.1016/j.carbpol.2012.07.085DOI Listing
January 2013

Triamcinolone solubilization by (2-hydroxypropyl)-β-cyclodextrin: A spectroscopic and computational approach.

Carbohydr Polym 2012 Oct 1;90(3):1288-98. Epub 2012 Jul 1.

Department of Pharmaceutical and Toxicological Chemistry, University of Naples Federico II, Via D. Montesano 49, 80131, Naples, Italy.

The molecular foundations of the use of (2-hydroxypropyl)-β-cyclodextrin (HPβCD) as solubility promoter of triamcinolone acetonide (TrA), a corticosteroid with very low aqueous solubility, was investigated by a multidisciplinary spectroscopic and computational approach. Aqueous solutions of TrA and HPβCD were investigated by UV and NMR spectroscopies. The association constant was determined by phase solubility diagrams and by the Foster-Fyfe method whereas the nature of the drug/cyclodextrin aggregates was probed by using the NMR DOSY technique. ROE measurements in solution led to stereochemical information regarding the nature of inclusion processes. TrA/HPβCD powders were prepared and investigated by Raman spectroscopy supported by computational methods. A molecular interaction of the hydroxyacyl chain with cyclodextrin, not identified in solution, was detected. Raman imaging experiments confirmed the attainment of a molecularly homogeneous system when the TrA/HPβCD molar ratio was 1:7 whereas TrA crystallized for mixtures richer in TrA (1:3.5) forming domains with size in the range of 10-15μm. We demonstrate that the combined use of several spectroscopical techniques with specific responsivities allows a detailed depiction of drug/cyclodextrin interaction useful in the development of novel pharmaceutical formulation.
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http://dx.doi.org/10.1016/j.carbpol.2012.06.075DOI Listing
October 2012

Mono- and bis-quinidine organocatalysts in the asymmetric methanolysis of cis-1,2,3,6-tetrahydrophthalic anhydride: a conformational and mechanistic NMR study.

Chirality 2011 Oct;23(9):784-95

Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Pisa, Italy.

The enantioselective organocatalytic methanolysis of cis-1,2,3,6-tetrahydrophthalic anhydride mediated by quinidine derivatives with pyridazine or anthraquinone core was investigated, carrying out a detailed nuclear magnetic resonance study of the conformational preferences of the alkaloid catalysts in the pure solvent and in the presence of the reaction substrates and products. No significant interaction between the meso-anhydride and the alkaloid derivatives was detected. In contrast, evidence for a considerable influence of the alcohol reactant on the conformational state of some of the chiral organocatalysts could be obtained, which lends support to the hypothesis of general-base catalysis mechanism, as opposed to the nuclephilic one. The catalytic properties of the studied derivatives showed no obvious correlation with their conformational prevalence in the resting state, suggesting that the alkaloid 9-O substituent should have a more active role than merely enforcing the chiral fragments to adopt a preferential reactive conformation. A strong enantioselective interaction between the enantiomers of the hemiester product and the alkaloid derivatives was also observed, leading to the conclusion that in the actual reaction conditions a relatively large fraction of the latter is in the protonated form.
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http://dx.doi.org/10.1002/chir.20993DOI Listing
October 2011

NMR enantiodiscrimination by pentafluorophenylcarbamoyl derivatives of quinine: C10 versus C9 derivatization.

Chirality 2011 May 23;23(5):417-23. Epub 2011 Mar 23.

Dipartimento di Chimica e Chimica Industriale, Università degli Studi di Pisa, I-56126 Pisa, Italy.

9-O-(Pentafluorophenylcarbamoyl)quinine and 10-(pentafluorophenylcarbamoyloxy)-6'-methoxy-11-norcinchonan-9-ol, obtained by derivatization of alkaloid double bond, were compared in NMR enantiodiscrimination experiments of selected chiral substrates.
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http://dx.doi.org/10.1002/chir.20945DOI Listing
May 2011

Water soluble heptakis(6-deoxy-6-thio)cyclomaltoheptaose capped gold nanoparticles via metal vapour synthesis: NMR structural characterization and complexation properties.

Carbohydr Res 2011 May 28;346(6):753-8. Epub 2011 Feb 28.

Dipartimento di Chimica e Chimica Industriale, Università degli Studi di Pisa, via Risorgimento 35, I-56126 Pisa, Italy.

The complexation of heptakis(6-deoxy-6-thio)cyclomaltoheptaose to gold nanoparticles prepared by using the Metal Vapour Synthesis (MVS) led to water soluble gold nanoaggregates, thermally stable at 25°C. The role of gold concentration in the MVS-derived starting solution as well as of the cyclodextrin to gold molar ratio on the size of cyclodextrin-capped gold nanoparticles were investigated. The ability of cyclodextrin bonded to gold nanoparticles to include deoxycytidine was also probed in comparison with that of 1-thio-β-D-glucose sodium salt.
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http://dx.doi.org/10.1016/j.carres.2011.02.001DOI Listing
May 2011

A nuclear magnetic resonance approach to the comparison of mucoadhesive properties of polysaccharides for ophthalmic uses.

Int J Pharm 2011 Mar 8;406(1-2):78-83. Epub 2011 Jan 8.

Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Via Risorgimento 35, I-56126 Pisa, Italy.

Mucoadhesive properties of tamarind seed polysaccharide (TSP) and larch arabinogalactan (AG), which are developed for ophthalmic applications, were investigated by NMR spectroscopy. Polysaccharide to mucin affinities were compared by using ketotifen fumarate as low molecular weight interaction probe. Proton selective relaxation rate measurements revealed enhanced affinity of TSP to mucin with respect to AG.
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http://dx.doi.org/10.1016/j.ijpharm.2010.12.032DOI Listing
March 2011

Synergistic interaction between TS-polysaccharide and hyaluronic acid: implications in the formulation of eye drops.

Int J Pharm 2010 Aug 24;395(1-2):122-31. Epub 2010 May 24.

Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Via Risorgimento 35, I-56126 Pisa, Italy.

An interaction between tamarind seed polysaccharide (TSP) and hyaluronic acid (HA) in aqueous solution has been ascertained. Various TSP/HA mixtures have been studied as the basis for the development of a potential excipient for eye drops synergistically improved over those of the separate polymers. Information about the nature of interpolymer interactions, and their dependence on TSP/HA ratios were obtained by NMR spectroscopy in solution. Superior mucin affinity of TSP/HA mixtures with respect to the single polysaccharides was assessed by NMR proton selective relaxation rate measurements. The mucoadhesivity of the TSP/HA (3/2) mixture, evaluated in vitro by NMR or viscometry, and in vivo by its mean and maximum residence time in rabbit precorneal area, is stronger than that of the component polysaccharides or the TSP/HA mixtures of different composition. TSP/HA (3/2) is little viscous and well tolerated by rabbit eyes. It stabilizes the tear film, thereby prolonging the residence of ketotifen fumarate and diclofenac sodium in tear fluid, but is unable to permeabilize the cornea. In conclusion, mucoadhesivity is responsible for the TSP/HA (3/2) synergistic enhancement of either extra- or intra-ocular drug bioavailability.
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http://dx.doi.org/10.1016/j.ijpharm.2010.05.031DOI Listing
August 2010

Stereoselective synthesis of beta-phenylselenoglycosides from glycals and rationalization of the selenoglycosylation processes.

J Org Chem 2010 Jun;75(12):4284-7

Dipartimento di Scienze Farmaceutiche, sede Chimica Biorganica e Biofarmacia, Università di Pisa,Via Bonanno 33, 56126 Pisa, Italy.

Beta-phenylselenoglycosides have been efficiently and stereoselectively synthesized by direct oxidative glycosylation of benzenselenolate (PhSe(-)) with glycals. A rationalization of the presently described beta-selectivity and the opposite alpha-selectivity reported by Danishefsky in the ring-opening of epoxy glycals with benzeneselenol (PhSeH) is proposed.
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http://dx.doi.org/10.1021/jo100145sDOI Listing
June 2010
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