Studio dell'attività antiossidante di miscele naturali e naturali-simile di fenoli nello sviluppo di terapie fitochimiche

Responsabili di progetto

Giovannamaria Delogu, Vessela Deneva Kancheva

Accordo

BULGARIA - BAS - Bulgarian Academy of Sciences

Bando

CNR-BAS 2016-2018

Dipartimento

Scienze chimiche e tecnologie dei materiali

Area tematica

Scienze chimiche e tecnologie dei materiali

Stato del progetto

Nuovo

Proposta di ricerca

The human body is constantly subjected to a significant oxidative stress as a result of the misbalance between antioxidant protective system and the formation of strong oxidizing substances (radical oxygen species, ROS), including free radicals. The stress damage DNA, proteins, lipids and carbohydrates and could cause negative effect on intracellular signal transmission. Free radicals are responsible for the pathogenesis of a wide range of diseases: the most serious and difficult to treat health problems such as cancer and cardiovascular diseases, neurodegenerative disorders, Parkinson's disease and dementia. ROS are also a common feature of insulin resistance generated by metabolite syndrome. In this respect the medical treatment of most of diseases includes formulations based on a combination of traditional drugs with targeted functionality and different antioxidants.
Nowadays the antioxidants play an important role in the prevention and treatment of certain diseases. Antioxidant therapy is a contemporary method which is effective in preventing the abnormal production of ROS and limiting their overall harmful impact on the body. Application of suitable antioxidants leads to a significant decrease of the lipid peroxidation and increases activity of the antioxidant protective enzyme system, thus reducing the oxidative stress and the negative consequences.Although the etiologic mechanisms of Parkinson's disease are poorly understood, recent reports implicate brain inflammation and oxidative stress play an important role in disease pathogenesis.
These evidences motivate researchers to investigate the effect of application of different therapies including phytochemical therapies. Natural compounds from fruits, vegetables and spices as curcumin, zingerone, dehydrozingerone, chorogenic acid, eugenol, eugenol dimer, apocynin, apocynin dimer, ferulic acid, honokiol, magnolol have been investigated in pathologies of social relevance. In virtue of the low toxicity and antioxidant activity of these natural occurring phenols, there is an interest in giving phenol mixtures to patients with neurodegenerative diseases and cancer, even to people affected by metabolic syndrome. The level of bioactive phytochemicals within the body is largely determined by diverse phenomena, such as the digestive transformation of native compounds, absorption in the intestine, hepatic activity, and biliary or urinary excretion. The hydroxycinnamic acid subclass was the main contributor to the total phenolic acid intake, accounting about 90%, thus, it is important to take in account also the antioxidant activity of metabolites of these natural phenols generated during the eating. Moreover, the opportunity of combination therapies based on natural products and approved drugs, such as the combination of curcumin and 5-fluorouracil, or the combination of two natural compounds such as thymol and geraniol or curcumin and piplartine has been successfully investigated. Although the growing interest in these mixtures and their potential use in medicinal applications, no information has been reported on their antioxidant activity in term of additivism (summary effect) or synergism (stronger effect) that results by the combinations of these compounds. Before entering the clinical trial phase which is very expensive, quantification of antioxidant synergy is an approach to generate fast, easy and robust data.
Taking into account known and efficient phytochemical therapies of which we will evaluate the antioxidant activity; we can propose novel phytochemical therapies by small modification of the natural compounds (for example, preparation of the equivalent hydroxylated biphenyl) through the study of their antioxidant activity.
The Italian group is expert in the design, synthesis and characterization of natural and natural-like phenols and in particular of hydroxylated biphenyls as effective agents for different applications in medicine and agriculture. It is generally acknowledged that hydroxylated biphenyls are privileged molecules for proteins binding in comparison to other aromatic compounds in virtue of the flexible biphenyl structure that can be accommodated, with high level of specificity, in a wide variety of pockets present on protein surfaces. This aspect can be useful in preparing new effective antioxidant phenol mixtures to be applied in phytochemical therapies. The Italian group presents expertise on detection of antioxidant capacity by electrochemical methods.
The Bulgarian group is expert in studying the structure-antiradical and antioxidant activity relationship of natural phenolic antioxidants and their synthetic analogues (including monomers and dimers). Various combination of experimental and theoretical approaches are applied to assess the antioxidant potential not only of individual compounds but also of binary and triple mixtures with alpha-tocopherol and/or ascorbic acid of a wide range of phenolic antioxidants. The main kinetic parameters of inhibited lipid autoxidation as antioxidant efficiency (means how many times the oxidative stability of lipid substrate increases) and antioxidant reactivity (means how many times the oxidation chain is shorten) in presence of antioxidants are determined as individuals and in mixtures. Modern quantum chemical calculations (DFT) are applied to optimize the geometry of various phenolic antioxidants and their phenoxyl radicals formed and the theoretical descriptors are determined. On this basis the prediction of antiradical and antioxidant activity of new phenolic compounds is possible.
The Bulgarian-Italian research group demonstrated the enhanced antioxidant activity of C2-symmetrical dimers of natural phenols (hydroxylated biphenyls) compared to the corresponding monomers and the efficiency of binary and ternary mixtures of phenols in combination with conventional antioxidants.

Obiettivi della ricerca

The main objective is to evaluate antioxidant activity of natural and natural-like phenol mixtures to be applied in pathologies with different etiologies and, all of them, characterized by ROS production like Parkinson's and Alzheimer's diseases, cancer and metabolic syndrome. The effect of phenol mixtures can enhance the effect of drugs generally used in these pathologies. Antioxidant activity of new effective antioxidant phenol mixtures (bio-antioxidants) could be evaluate for a potential application in phytochemical therapies or in specific diets recommended for metabolic syndromes like obesity-related disorders.
The specific objectives include:
(1) Studies of antioxidant activity of natural occurring phenol mixtures efficient in phytochemical therapies.
(2) Design, preparation and characterization of natural-like phenols and dimers to be used in mixture in order to increase antioxidant activity of the phenol mixtures detected at point (1). Some of these phenols are metabolites of naturally occurring compounds generated by human intestinal microbiota.
(3) Evaluation of antioxidant activity of phenol mixtures prepared at point (2). The antioxidant activity of some of these phenol mixtures will be studied in combination with common drugs.
(4) Computational study aimed to investigate the effect of functional groups on the structure and the electronic properties (lipophilicity and antioxidant capacity) of the new molecules will be undertaken.

Ultimo aggiornamento: 11/05/2025