SMALL AND LARGE MOLECULES: SUSTAINABLE SYNTHESIS, DESIGN AND BIOMEDICAL APPLICATIONS Istituto di Chimica Biomolecolare, UOS DI CATANIA - Via Paolo Gaifami, 18 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. Nitrilase, nitrile hydratase and amidase: hydrolytic enzymes capable of transforming stereoselectively the nitrile group in the carboxyl group in mild reaction conditions. 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 (+)-Cyclophellitol b-Glucosidase inhibitor And Anti-HIV agent Profens anti-inflammatory drugs (NSAIDs) 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 Enzymatic and chemical enantiomeric resolution 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, D L stereoselectivity, low cost and the “green features” typical of biocatalytic methodologies. 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. Lipase-catalyzed kinetic resolution of racemic mixtures 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 Synthetic applications Lipases are able to transform the enantiomers of a racemic mixture with different reaction rate. Ferrocenyl derivatives Precursors of biologically active compounds D’Antona, N.; Morrone, R.; Bovicelli, P.; Gambera G.; Kubáč, D.; Martínková, L. Tetrahedron: Asymm. 2010, 21, 2448 Acting on reaction conditions it is possible to improve the lipase stereoselectivity. D’Antona, N.; Morrone, R.; Nicolosi, G.; Pedotti, S. RSC Adv 2013, 3, 11456 Martínková, L; Stolz, A.; Van Rantwijk, F.; D’Antona, N.; Brady, D.; Otten, L.G. Riva, S.; Fessner, W.F; Wiley, 2014, 249 bipyridines milnacipran Lipases are even able to transform selectively opposite chiral centers present in the same molecule (desymmetrization of meso forms) 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. 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. bipyridines milnacipran zingerol zingerol Zingerol dimer Zingerol dimer Sanfilippo, C., Nicolosi, G., Patti, A. Curr. Org. Chem. 2012, 16, 1636 Sanfilippo, C., Patti, A., Dettori, M.A., Fabbri, D., Delogu, G. J. Mol. Catal. B: Enzym. 2013, 90, 107 unreacted substrates acylated products Sanfilippo, C., Nicolosi, G., Patti, A. J. Mol. Catal. B: Enzym. 2014, 104, 82 Resolution of planar chirality via asymmetric reduction 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. Synthesis of Glycerophosphoinositol (GPI) Derivatives parallel kinetic resolution 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). Patti, A.; Pedotti, S. Tetrahedron:Asymmetry 2010, 21, 2631-2637 Fluorescent probes Sustainable synthesis GPI analogues stabilised toward the hydrolytic action of phosphodiesterases Greco, G.; D’Antona, N.; Gambera, G.; Nicolosi, G. Synlett. 2014, 25. a natural compound PON 01_00862 : An integrated technological platform for the development of new drugs for rare diseases «on water» reactivity Novel catalysts for asymmetric synthesis 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 Lipase-catalyzed green oxidation of C=C double bond 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. Chemical step oxidation of C=C bond Patti, A.; Pedotti, S. Tetrahedron 2010, 66, 5607-5611 A family of ferrocene-proline conjugates was synthesized and evaluated for their catalytic activity in the asymmetric aldol the catalyst (5% mol) 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 Enzymatic step Lipase-catalyzed acid oxidation Tested for antimalarial activity the product 90-94% ee Patti, A.; Pedotti, S. Eur. J. Org. Chem. 2014, 624-630 doubled activity compared with the phenyl analogues Reductive intramolecular cyclization ONE-POT Patti, A.; Pedotti, S. T. Grassi, A. Idolo, M. Guido, A. De Donno J. Organomet. Chem. 2012, 716, 216-221 Patti, A.; Pedotti, S. J. Sep. Sci. 2014, in press, DOI: 10.1002/jssc.201400838 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 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. From molecular recognition to biomedical devices Calixarenes as scaffolds to build potential anticancer vaccines PDTRP 50000 PDTRP Fluorescence (AU) PDTRP Calixarene-based Drug Delivery Systems A,B 37500 25000 D,E D,E 12500 Heparin Iπποκράτης C8 15 deriv. C4 4 deriv. 8x 4x 1x Control Mice (HIPPOCRATES) + DRUG 16 Monovalent reference compound Cell recognition analysis for specific antiMUC1 antibodies tested on MCF7 human breast cancer cells. No antibody binding was observed for SK-MEL-28 cell. Calix[4]arene engineered for selective tumor cell imaging 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… …. topical ophtalmic application D,E 0 P3CS 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 Sicily Technologic District Micro and Nano Systems C Development of antithrombogenic materials and blood filters C8-Lysine Development of Micro and Nano-technologies and Advanced Systems to the Men’s Health Polycationic calix[8]arene receptors grafted onto polymeric matrix: smart material for heparin neutralization Tommaso Mecca, Francesca Cunsolo, Polym. Adv. Technol. 2010, 21, 752757 pH-sensitive hydrogel (pH 4.5-5) Potential drug delivery systems for… Physiological pH Dissolution and drug release C8-Lysine – Heparin complex 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 …….ocular diseases Filter …..hepatocarcinoma + DRUG …to Selected for Patent Application + DRUG DH 100 nm DH 200 nm ASGP-R D-galactose receptor • Colloidal solution • High drug loading capacity • Low corneal cell toxicity Highly selective tumor cell uptake Fluorescent labeled folate–calixarene conjugate • Antibacterial activity 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 Development of a Heparin filter for dialysis applications
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