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Synthesis of chiral compounds Chirality is a fundamental dimension for biological activity and there is a growing demand for synthetic methods leading to single or enriched enantiomers. Chemical modification of “chiral pool” can be advantageously exploited for the synthesis of compounds with multiple stereogenic centres starting from relatively inexpensive and renewable source of chirality. the catalyst (5% mol) the product 90-94% ee «on water» reactivity Asymmetric catalytic synthesis is a powerful strategy for the generation of stereogenic centre(s) starting from achiral compounds and the stereoselective construction of molecular complexity through the intermolecular chirality transfer from a chemical catalyst, which can be suitable designed to maximize the efficiency of the process. A family of ferrocene-proline conjugates was synthesized and evaluated for their catalytic activity in the asymmetric aldol condensation in water. The introduction of the ferrocenyl moiety led to enhanced efficiency in comparison with the proline. The reaction proceeded in “on water” conditions and displayed broad substrate scope and high enantioselectivity Patti, A.; Pedotti, S. Eur. J. Org. Chem. 2014, 624-630 Patti, A.; Pedotti, S. J. Sep. Sci. 2014, in press, DOI: 10.1002/jssc.201400838 Synthesis of Glycerophosphoinositol (GPI) Derivatives PON 01_00862 : An integrated technological platform for the development of new drugs for rare diseases Glycerophosphoinositols (GPIs) are a class of naturally occurring metabolites with effects on cell proliferation, motility and invasiveness. They are catabolised/inactivated by glycerophosphodiester phosphodiesterases (GDEs). Novel catalysts for asymmetric synthesis a natural compound GPI analogues stabilised toward the hydrolytic action of phosphodiesterases Greco, G.; D’Antona, N.; Gambera, G.; Nicolosi, G. Synlett. 2014, 25. Fluorescent probes SMALL AND LARGE MOLECULES: SUSTAINABLE SYNTHESIS, DESIGN AND BIOMEDICAL APPLICATIONS Istituto di Chimica Biomolecolare, UOS DI CATANIA - Via Paolo Gaifami, 18 Enzymatic and chemical enantiomeric resolution Nitrilase, nitrile hydratase and amidase: hydrolytic enzymes capable of transforming stereoselectively the nitrile group in the carboxyl group in mild reaction conditions. Synthetic applications (+)-Cyclophellitol b-Glucosidase inhibitor And Anti-HIV agent Profens anti-inflammatory drugs (NSAIDs) Ferrocenyl derivatives Precursors of biologically active compounds Lipases: in absence of water are able to reverse their physiological activity and stereoselectively catalyze esterification, alcoholysis, transacylations and aminolysis reactions in mild conditions. In organic solvent the direct esterification of a carboxylic acid is irreversible in the presence of alkyl carbonates and alkyl orthoformates that remove the formed water Chemical modification of natural compounds for phytotherapic/nutraceutical applications, synthesis of intermediates and products with pharmacological interest require the development of highly efficient and selective methodologies in order to minimize waste and purification steps. Chiral compounds additionally demand high optical purity since biological activity often resides in only one enantiomer of the molecule. In this context, the research activity is focused on the development of sustainable synthetic methodologies by means of the use of ecocompatible solvents, biocatalyzed transformations and asymmetric catalytic synthesis. Biocatalysis Hydrolytic enzymes are widely employed in organic synthesis due to their high chemo-, regio- and stereoselectivity, large substrate acceptance, stability in both aqueous and organic solvent, relatively low cost and the possibility to modulate their activity by solvent engineering or the use of suitable additives. Synthetic applications Martínková, L; Stolz, A.; Van Rantwijk, F.; D’Antona, N.; Brady, D.; Otten, L.G. Riva, S.; Fessner, W.F; Wiley, 2014, 249 D’Antona, N.; Morrone, R.; Bovicelli, P.; Gambera G.; Kubáč, D.; Martínková, L. Tetrahedron: Asymm. 2010, 21, 2448 D’Antona, N.; Morrone, R.; Nicolosi, G.; Pedotti, S. RSC Adv 2013, 3, 11456 Morrone, R.; D'Antona, N.; Biondi, D.; Lambusta, D.; Nicolosi, G. J. Mol. Cat. B: Enzymatic 2012, 84, 173 Morrone, R.; D'Antona, N.; Lambusta, D.; Nicolosi, G. J. Mol. Cat. B: Enzymatic 2010, 65, 49 In same instances chemical catalysts have been also employed in racemate resolution through the conversion of the two enantiomers into a couple of diastereoisomers by generation of new stereogenic centers. Kinetic resolution is a widely used procedure in organic chemistry to separate the enantiomers of a racemic mixture exploiting the differences of reactivity between the two optical antipodes towards reagents or chiral catalysts. Enzymatic catalysis is a valuable approach for its versatility, stereoselectivity, low cost and the “green features” typical of biocatalytic methodologies. Lipases are able to transform the enantiomers of a racemic mixture with different reaction rate. Acting on reaction conditions it is possible to improve the lipase stereoselectivity. Lipases are even able to transform selectively opposite chiral centers present in the same molecule (desymmetrization of meso forms) Multivalency is the strategy that nature utilizes to increase avidity, specificity, and selectivity in molecular recognition events. Calix[n]arene macrocycles, which offer oligomers with different size, shape and conformational flexibility, are promising molecular platforms to be engineered for biomedical applications. The research activity is focused on the development of large multivalent molecules able to act as ligands of biologically relevant species and assemble in supramolecular nanostructures useful for nanomedicine applications. Polycationic calix[8]arenes able to recognize and neutralize heparin Tommaso Mecca, Grazia M. L. Consoli, Corrada Geraci, Rita La Spina, Francesca Cunsolo, Org. Biomol. Chem. 2006, 4, 3763-3768 C8-Lysine Heparin C8-Lysine Heparin complex Polycationic calix[8]arene receptors grafted onto polymeric matrix: smart material for heparin neutralization Tommaso Mecca, Francesca Cunsolo, Polym. Adv. Technol. 2010, 21, 752- 757 Development of antithrombogenic materials and blood filters Biocompatible macroporous cryogel able to sequester heparin Chemically modified poly(2-hydroxyethyl methacrylate) cryogel for the adsorption of heparin Rita La Spina, Carla Tripisciano, Tommaso Mecca, Francesca Cunsolo, Viktoria Weber, Bo Mattiasson J. Biomed. Mat. Res. B 2014, 102, 1207-1216 Filter Development of a Heparin filter for dialysis applications From molecular recognition to biomedical devices Calixarene-based Drug Delivery Systems Colloidal solution High drug loading capacity Low corneal cell toxicity Antibacterial activity …….ocular diseases + DRUG Selected for Patent Application D H 100 nm …..hepatocarcinoma ASGP-R D-galactose receptor + DRUG D H 200 nm Physiological pH Dissolution and drug release pH-sensitive hydrogel (pH 4.5-5) …. topical ophtalmic application + DRUG Sicily Technologic District Micro and Nano Systems Iπποκράτης (HIPPOCRATES) Development of Micro and Nano-technologies and Advanced Systems to the Men’s Health Potential drug delivery systems for… Highly selective tumor cell uptake Design, synthesis, and drug solubilising properties of the first folatecalix[4]arene conjugate Grazia M. L. Consoli, Giuseppe Granata, Corrada Geraci Org. Biomol. Chem. 2011, 9, 64916495 From this result… …to Fluorescent labeled folatecalixarene conjugate Calix[4]arene engineered for selective tumor cell imaging Calixarenes as scaffolds to build potential anticancer vaccines Cell recognition analysis for specific anti- MUC1 antibodies tested on MCF7 human breast cancer cells. No antibody binding was observed for SK-MEL-28 cell. 0 12500 25000 37500 50000 8x 4x 1x Control Mice Fluorescence (AU) C8 deriv. C4 deriv. Monovalent reference compound First self-adjuvant multicomponent potential vaccine candidates by tethering of four or eight MUC1 antigenic immunodominant PDTRP units on a calixarene platform: synthesis and biological evaluation Corrada Geraci, Grazia M. L. Consoli, Giuseppe Granata, Eva Galante, Angelo Palmigiano, Maria Pappalardo, Salvatore D. Di Puma, Angelo Spadaro Bioconjugate Chem. 2013, 24, 1710−1720 PDTRP PDTRP PDTRP P 3 CS Sustainable synthesis In sustainable synthesis central emphasis need to be given to waste prevention, reduced energy requirements and low toxicity for human health and environment. In this context, multicomponent and cascade reactions, microwave assisted synthesis and the use of water as solvent offer valuable contributes. Resolution of planar chirality via asymmetric reduction Patti, A.; Pedotti, S. Tetrahedron:Asymmetry 2010, 21, 2631-2637 Reductive intramolecular cyclization ONE-POT Patti, A.; Pedotti, S. Tetrahedron 2010, 66, 5607-5611 Novel biomimetic oxidant systems based on hydrogen peroxide are promising alternatives to the current process for their high atom economy and the production of water as the only by-product Chemical step oxidation of C=C bond Enzymatic step Lipase-catalyzed acid oxidation Lipase-catalyzed green oxidation of C=C double bond D L Lipase-catalyzed kinetic resolution of racemic mixtures unreacted substrates acylated products Sanfilippo, C., Nicolosi, G., Patti, A. Curr. Org. Chem. 2012, 16, 1636 Sanfilippo, C., Nicolosi, G., Patti, A. J. Mol. Catal. B: Enzym. 2014, 104, 82 Sanfilippo, C., Patti, A., Dettori, M.A., Fabbri, D., Delogu, G. J. Mol. Catal. B: Enzym. 2013, 90, 107 milnacipran bipyridines zingerol Zingerol dimer milnacipran bipyridines zingerol Zingerol dimer The oxazaborolidine catalyst promoted the stereoselective reduction of carbonyl group in the substrate and the efficiency of the asymmetry induction was not influenced by the pre-existing chirality in the substrate. parallel kinetic resolution Starting from a variety of functionalized aldehydes and ketones, tetrahydroquinolines or quinolines can be selectively obtained by simple modification of the experimental conditions (solvent, hydrogen source). The heteroaromatic scaffold is present in a variety of biologically active compounds Tested for antimalarial activity doubled activity compared with the phenyl analogues Patti, A.; Pedotti, S. T. Grassi, A. Idolo, M. Guido, A. De Donno J. Organomet. Chem. 2012, 716, 216-221

SMALL AND LARGE MOLECULES: SUSTAINABLE SYNTHESIS, …€¦ · The introduction of the ferrocenyl moiety led to enhanced efficiency in comparison with the proline. The reaction proceeded

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  • Synthesis of chiral compounds Chirality is a fundamental dimension for biological activity and there is a

    growing demand for synthetic methods leading to single or enriched

    enantiomers.

    Chemical modification of “chiral pool” can be advantageously exploited for

    the synthesis of compounds with multiple stereogenic centres starting from

    relatively inexpensive and renewable source of chirality.

    the catalyst

    (5% mol)

    the product

    90-94% ee

    «on water»

    reactivity

    Asymmetric catalytic synthesis is a powerful strategy for the generation of stereogenic

    centre(s) starting from achiral compounds and the stereoselective construction of molecular

    complexity through the intermolecular chirality transfer from a chemical catalyst, which can be

    suitable designed to maximize the efficiency of the process.

    A family of ferrocene-proline conjugates was synthesized and

    evaluated for their catalytic activity in the asymmetric aldol

    condensation in water. The introduction of the ferrocenyl

    moiety led to enhanced efficiency in comparison with the

    proline. The reaction proceeded in “on water” conditions and

    displayed broad substrate scope and high enantioselectivity

    Patti, A.; Pedotti, S. Eur. J. Org. Chem. 2014, 624-630

    Patti, A.; Pedotti, S. J. Sep. Sci. 2014, in press, DOI: 10.1002/jssc.201400838

    Synthesis of Glycerophosphoinositol (GPI) Derivatives

    PON 01_00862 :

    An integrated technological platform for the

    development of new drugs for rare diseases

    Glycerophosphoinositols (GPIs) are a class of naturally occurring metabolites

    with effects on cell proliferation, motility and invasiveness. They are

    catabolised/inactivated by glycerophosphodiester phosphodiesterases (GDEs).

    Novel catalysts for asymmetric synthesis

    a natural compound

    GPI analogues stabilised toward the hydrolytic

    action of phosphodiesterases

    Greco, G.; D’Antona, N.; Gambera, G.;

    Nicolosi, G. Synlett. 2014, 25.

    Fluorescent probes

    SMALL AND LARGE MOLECULES:

    SUSTAINABLE SYNTHESIS, DESIGN

    AND BIOMEDICAL APPLICATIONS

    Istituto di Chimica Biomolecolare,

    UOS DI CATANIA - Via Paolo Gaifami, 18

    Enzymatic and chemical enantiomeric resolution Nitrilase, nitrile hydratase and amidase:

    hydrolytic enzymes capable of transforming

    stereoselectively the nitrile group in the carboxyl

    group in mild reaction conditions.

    Synthetic applications

    (+)-Cyclophellitol

    b-Glucosidase inhibitor

    And Anti-HIV agent

    Profens

    anti-inflammatory

    drugs (NSAIDs)

    Ferrocenyl derivatives

    Precursors of biologically

    active compounds

    Lipases: in absence of water are able to reverse their physiological

    activity and stereoselectively catalyze esterification, alcoholysis,

    transacylations and aminolysis reactions in mild conditions.

    In organic solvent the direct esterification of a carboxylic acid is

    irreversible in the presence of alkyl carbonates and alkyl orthoformates

    that remove the formed water

    Chemical modification of natural compounds for phytotherapic/nutraceutical applications, synthesis of intermediates and products with pharmacological interest require the

    development of highly efficient and selective methodologies in order to minimize waste and purification steps. Chiral compounds additionally demand high optical purity since biological activity often resides in only one enantiomer of the molecule. In this context, the research activity is focused on the development of sustainable synthetic methodologies by means of the use of ecocompatible solvents, biocatalyzed transformations and asymmetric catalytic synthesis.

    Biocatalysis Hydrolytic enzymes

    are widely employed

    in organic synthesis

    due to their high

    chemo-, regio- and stereoselectivity, large substrate

    acceptance, stability in both

    aqueous and organic solvent,

    relatively low cost and the

    possibility to modulate their

    activity by solvent engineering

    or the use of suitable additives. Synthetic applications

    Martínková, L; Stolz, A.; Van Rantwijk, F.; D’Antona, N.; Brady, D.; Otten, L.G. Riva, S.; Fessner, W.F; Wiley, 2014, 249

    D’Antona, N.; Morrone, R.; Bovicelli, P.; Gambera G.; Kubáč, D.; Martínková, L. Tetrahedron: Asymm. 2010, 21, 2448

    D’Antona, N.; Morrone, R.; Nicolosi, G.; Pedotti, S. RSC Adv 2013, 3, 11456

    Morrone, R.; D'Antona, N.; Biondi, D.; Lambusta, D.; Nicolosi, G. J. Mol. Cat. B: Enzymatic 2012, 84, 173

    Morrone, R.; D'Antona, N.; Lambusta, D.; Nicolosi, G. J. Mol. Cat. B: Enzymatic 2010, 65, 49

    In same instances chemical catalysts have been also employed in racemate resolution through the conversion of the two enantiomers into a couple of diastereoisomers by generation of new stereogenic centers.

    Kinetic resolution is a widely used procedure in organic chemistry to separate the enantiomers of

    a racemic mixture exploiting the differences of reactivity between the two optical antipodes

    towards reagents or chiral catalysts. Enzymatic catalysis is a valuable approach for its versatility, stereoselectivity, low cost and the “green features” typical of biocatalytic methodologies.

    Lipases are able to transform the

    enantiomers of a racemic mixture with

    different reaction rate.

    Acting on reaction conditions it is

    possible to improve the lipase

    stereoselectivity.

    Lipases are even able to transform

    selectively opposite chiral centers

    present in the same molecule

    (desymmetrization of meso forms)

    Multivalency is the strategy that nature utilizes to increase avidity, specificity, and selectivity in molecular recognition events. Calix[n]arene macrocycles, which offer

    oligomers with different size, shape and conformational flexibility, are promising molecular platforms to be engineered for biomedical applications. The research activity is

    focused on the development of large multivalent molecules able to act as ligands of biologically relevant species and assemble in supramolecular nanostructures useful for

    nanomedicine applications.

    Polycationic calix[8]arenes able to recognize and neutralize heparin

    Tommaso Mecca, Grazia M. L. Consoli, Corrada Geraci, Rita La

    Spina, Francesca Cunsolo,

    Org. Biomol. Chem. 2006, 4, 3763-3768

    C8-Lysine

    Heparin

    C8-Lysine – Heparin complex

    Polycationic calix[8]arene receptors

    grafted onto polymeric matrix: smart

    material for heparin neutralization

    Tommaso Mecca, Francesca Cunsolo,

    Polym. Adv. Technol. 2010, 21, 752-

    757

    Development of antithrombogenic

    materials and blood filters

    Biocompatible macroporous

    cryogel able to sequester heparin Chemically modified poly(2-hydroxyethyl methacrylate)

    cryogel for the adsorption of heparin

    Rita La Spina, Carla Tripisciano, Tommaso Mecca,

    Francesca Cunsolo, Viktoria Weber, Bo Mattiasson

    J. Biomed. Mat. Res. B 2014, 102, 1207-1216

    Filter

    Development of a Heparin

    filter for dialysis applications

    From molecular recognition to biomedical devices

    Calixarene-based Drug Delivery Systems

    • Colloidal solution

    • High drug loading capacity

    • Low corneal cell toxicity

    • Antibacterial activity

    …….ocular diseases

    + DRUG

    Selected for Patent

    Application DH 100 nm

    …..hepatocarcinoma

    ASGP-R D-galactose receptor

    + DRUG

    DH 200 nm

    Physiological pH

    Dissolution and drug release

    pH-sensitive hydrogel (pH 4.5-5)

    …. topical ophtalmic application

    + DRUG

    Sicily Technologic District Micro and Nano Systems

    Iπποκράτης

    (HIPPOCRATES)

    Development of Micro and Nano-technologies

    and Advanced Systems to the Men’s Health

    Potential drug delivery

    systems for…

    Highly selective tumor cell uptake

    Design, synthesis, and drug solubilising properties of the

    first folate–calix[4]arene conjugate

    Grazia M. L. Consoli, Giuseppe Granata, Corrada Geraci

    Org. Biomol. Chem. 2011, 9, 6491–6495

    From this result… …to

    Fluorescent labeled

    folate–calixarene conjugate

    Calix[4]arene engineered for

    selective tumor cell imaging

    Calixarenes as scaffolds to build

    potential anticancer vaccines

    Cell recognition analysis for specific anti-

    MUC1 antibodies tested on MCF7 human

    breast cancer cells. No antibody binding was

    observed for SK-MEL-28 cell.

    0

    12500

    25000

    37500

    50000

    15 4 8x 4x 1x ControlMice

    Flu

    ore

    sce

    nce

    (AU

    )

    16

    A,B

    C

    D,E D,ED,E

    C8

    deriv.

    C4

    deriv.

    Monovalent reference compound

    First self-adjuvant multicomponent potential vaccine

    candidates by tethering of four or eight MUC1 antigenic

    immunodominant PDTRP units on a calixarene platform:

    synthesis and biological evaluation

    Corrada Geraci, Grazia M. L. Consoli, Giuseppe

    Granata, Eva Galante, Angelo Palmigiano, Maria

    Pappalardo, Salvatore D. Di Puma, Angelo Spadaro

    Bioconjugate Chem. 2013, 24, 1710−1720

    PDTRP

    PDTRP PDTRP

    P3CS

    Sustainable synthesis In sustainable synthesis central emphasis need to be

    given to waste prevention, reduced energy

    requirements and low toxicity for human health and

    environment. In this context, multicomponent and

    cascade reactions, microwave assisted synthesis and

    the use of water as solvent offer valuable contributes.

    Resolution of planar chirality via asymmetric reduction

    Patti, A.; Pedotti, S. Tetrahedron:Asymmetry 2010, 21, 2631-2637

    Reductive intramolecular cyclization

    ONE-POT

    Patti, A.; Pedotti, S. Tetrahedron 2010, 66, 5607-5611

    Novel biomimetic oxidant systems based on hydrogen peroxide are

    promising alternatives to the current process for their high atom economy

    and the production of water as the only by-product

    Chemical step

    oxidation of C=C bond

    Enzymatic step

    Lipase-catalyzed acid oxidation

    Lipase-catalyzed green oxidation of C=C double bond

    D L

    Lipase-catalyzed kinetic resolution of racemic mixtures

    unreacted substrates acylated products

    Sanfilippo, C., Nicolosi, G., Patti, A. Curr. Org. Chem. 2012, 16, 1636

    Sanfilippo, C., Nicolosi, G., Patti, A. J. Mol. Catal. B: Enzym. 2014, 104, 82

    Sanfilippo, C., Patti, A., Dettori, M.A., Fabbri, D., Delogu, G.

    J. Mol. Catal. B: Enzym. 2013, 90, 107

    milnacipran bipyridines

    zingerol

    Zingerol dimer

    milnacipran

    bipyridines

    zingerol Zingerol dimer

    The oxazaborolidine catalyst promoted

    the stereoselective reduction of

    carbonyl group in the substrate and the

    efficiency of the asymmetry induction

    was not influenced by the pre-existing

    chirality in the substrate.

    parallel kinetic resolution

    Starting from a variety of functionalized

    aldehydes and ketones, tetrahydroquinolines

    or quinolines can be selectively obtained by

    simple modification of the experimental

    conditions (solvent, hydrogen source).

    The heteroaromatic scaffold is present in a

    variety of biologically active compounds

    Tested for antimalarial activity doubled activity compared with the

    phenyl analogues

    Patti, A.; Pedotti, S. T. Grassi, A. Idolo, M. Guido, A.

    De Donno J. Organomet. Chem. 2012, 716, 216-221

    http://www.google.it/url?sa=i&rct=j&q=balb+mice&source=images&cd=&docid=gqYMtSV8SOLijM&tbnid=RkR-DdowiQNqeM:&ved=0CAUQjRw&url=http://jaxmice.jax.org/strain/003303.html&ei=G4naUZmPNMWROI3ZgLAH&bvm=bv.48705608,d.ZWU&psig=AFQjCNEYfhwOWXZTb7p9Myfj6QylsqLYbw&ust=1373362833771246http://www.google.it/url?sa=i&source=images&cd=&cad=rja&docid=IHUorIGqQcDJsM&tbnid=Z54_uSMxsJjKjM:&ved=0CAgQjRwwAA&url=http://www.bioblog.it/2006/04/06/vaccino-contro-il-papilloma-virus-hpv/200698&ei=bInaUaumFKvW7QaqgIHoBQ&psig=AFQjCNHILicvJDTHIDPK7SWD6ID06OEkIw&ust=1373362924372909http://www.google.it/url?sa=i&rct=j&q=piastre+ELISA&source=images&cd=&cad=rja&docid=P6biYvM7Wsx1MM&tbnid=VEEDwkYRyBrYiM:&ved=0CAUQjRw&url=http://www.sodipro.fr/catalogue/fiche-mat.php?refart=2330531&ei=soraUYi7KYG-PbmugSA&psig=AFQjCNHwRDeXocu561V-glpT1hDcBUzwiQ&ust=1373363217066576