small and large molecules: sustainable synthesis, …€¦ · the introduction of the ferrocenyl...
TRANSCRIPT
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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
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