LIFE-EDESIA project: overview and Actions B3, B5 ...old.iss.it/binary/life/cont/7._FIORINO_FRECENTESE.pdf · LIFE-EDESIA project: overview and Actions B3, B5 ... University of Naples“Federico

Endocrine Disruptors in silico / in vitro

Evaluation and Substitution for

Industrial Applications

LIFE12-ENV/IT/000633

Ferdinando Fiorino

Francesco Frecentese

Università degli Studi di Napoli Federico II (UniNA)

Department of Pharmacy

Unit of Medicinal Chemistry

LIFE-EDESIA project:

overview and Actions B3, B5

LIFE-EDESIA kick-off meeting Rome, October 14th

2013

Lab Profile

Principal Investigators

Elisa Perissutti, Ferdinando Fiorino,

Giuseppe Caliendo, Vincenzo Santagada






2013

Department of Pharmacy

University of Naples“Federico II”, Italy

Francesco Barbato,

Lucia Grumetto

Synthesis of the novel

chemical entities

Determination of the

technological features

and usability

Lab Profile

Working experience

Our research group has been always involved in medicinal chemistry

field. The research of our group is essentially related to design and

synthesis of novel heterocyclic compounds, peptides and peptide-

mimetic derivatives to be used as anti-inflammatory agents,

serotoninergic ligands, protease inhibitors as antitumoral and antiviral

agents.






2013

From several years our interest has been focused

on the application of microwave assisted organic

chemistry to the synthesis of pharmacologically

active compounds.

The LIFE EDESIA project aims to contribute to improve implementation of the REACH

Regulation by providing at least one suitable alternative for bisphenol A/BPA,

phthalates and parabens.

These objectives will be achieved by the following actions:;

Workplan






2013

….Synthesizing the selected substitutive chemicals; Creating

prototypes that use the substitutive chemicals, and to assess

them for release of chemicals; and Demonstrating the

feasibility of the substitution of the EDCs considered in the

project in industrial applications.

Activities in EDESIA






2013

ACTION B.3: Synthesis of the chemicals

The synthesis will be performed applying the most modern techniques

of organic synthesis, developed with particular attention to the

environmental impact. Advanced synthetic technologies, such as

microwave reactors specifically designed for organic synthesis and all

those technologies that allow to perform reactions both in the

presence of solvents, such as ionic liquids, alternative to common

volatile organic solvents , and in "solvent free" conditions will be used

(" Green chemistry ").







2013

The synthesized molecules will be accurately characterized in order to

acquire useful information to streamline their technological characteristics

of usability and interaction with living matter. In particular:

This Action will start at month 14 and finish at month 19

Definition of lipophilicity to different pH values of physiological relevance;

Determination of affinity values for membrane phospholipids and for the

serum-proteins;

Profiles of solubility in water at various pH;

Characterization of possible decomposition products;

Development of analytical methods useful for the determination of trace

products in biological matrices.


Task B.5: Prototyping and testing for industrial purposes in 3

application domains Preservatives are widely used, beside in food industry, in both cosmetic

and pharmaceutical fields. The use is mainly requested for products

containing water to control microbiological growth. It is important to

underline that even products based on lipophilic matrices often need the

addiction of preservatives since they can include more or less relevant

percentages of water. This means that preservatives must be added in a

large majority of cosmetic and pharmaceutical preparations, e.g. both

liquid and semisolid (lotions and creams, respectively) water in oil or oil

in water emulsions, hydrophilic ointments, and even water-absorbing

lipophilic ointments.






2013

More relevant for public health is the addiction of preservatives in orally

dosage forms such as syrups, often intended for children medication. To

date, parabens, the most widely used preservatives, can be replaced (in

some cases) by other preservatives, but these compounds show more

restricted microbiological properties and application suitability. Better

application profiles may be achieved by the new “paraben-like”

compounds synthesized in the present project.

Suitability in both cosmetic and pharmaceutical fields will be tested by

their inclusion in cosmetic and pharmaceutical preparations,

characterized by known composition and possibly already marketed.

Their antimicrobial efficacy in these different matrices will be also

evaluated as time function. This action will start at month 28 and finish at month 33.







2013

Tools

Medicinal Chemistry can be a

useful tool to get an answer to

the first end-point






2013






2013

CHEMICAL STRUCTURES OF SOME PHTALATE AND PARABEN DERIVATIVES

Dibutyl phthalate (DBP) Propylparaben

Diisopropyl phthalate (DIP) Butylparaben

bis(2-ethylhexyl) phthalate (DEHP)

n-butyl benzyl phthalate (BBP)

Research infrastructure

Microwave oven specifically designed for Organic Synthesis

Microwave oven specifically designed for Combichem

Preparative and analytical HPLC

LCQ ion trap mass spectrometer

API 2000 triple quadrupole mass spectrometer

NMR spectrometer 400, 500 and 700 Mhz






2013

SM-15811: IC30 17 nM

O

N O 2

S

N H

H 3 C H 2 C O O C

– Fast heating allows higher number of

componds

– Use of combinatorial chemistry

approches combined enhances library

generation

– Higher yields obtained

– Greener procedures allowed

Advantages Microwave heating

Why is it so popular among Medicinal Chemists?

The identification of a lead

compound starting from a larger

compound library is easier.

Just One winning compound

(Drug Candidate)

Compound Libraries






2013

Its basic principle is to conduct chemical reactions simultaneously, protecting the environment,

through the use of chemical processes deemed suitable to avoid pollution. In this contest, water

as solvent is a good option because of its abundant, non-toxic, non-corrosive, and non-

flammable nature.

Green Chemistry is the utilization of a set of principles

that reduce or eliminate the use or generation of hazardous substances in chemistry.

Although microwave assisted reactions in conventional solvents have

developed rapidly, the center of attention has recently shifted to

environmentally benign processes.

The association with microwaves allows to overcame

problems related to water traditional chemistry such as

insolubility of most of organic reactants or difficulty in the

product isolation from aqueous reaction mixture. In later

years various examples of reaction accelerations, selectivity,

and higher yields have been reported using water as solvent

or in some cases without the use of any solvent (solvent

free reactions).






2013






2013

LIFE-EDESIA project: overview and Actions B3, B5 ...old.iss.it/binary/life/cont/7._FIORINO_FRECENTESE.pdf · LIFE-EDESIA project: overview and Actions B3, B5 ... University of Naples“Federico

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