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