Synthesis of novel vanillin derivatives: study of their antioxidant and potential neuroprotective properties.

Vanillin (4-hydroxy-3-methoxybenzaldehyde) is a naturally-occurring phenolic compound, forming the main component of the bean and pod of vanilla orchids. It is widely used as a flavouring agent in food and drinks, and as a preservative in the cosmetic and pharmaceutical industries. In the past decades, several studies have reported on the antioxidant and protective effects of vanillin in several oxidative stress models, both in vitro and in vivo. The aim of this thesis was to synthesise novel vanillin derivatives with enhanced antioxidant properties and to study their potential neuroprotective activities in oxidative stress models in vitro. To achieve this aim, novel vanillin derivatives were synthesised through a reductive amination reaction, by reacting vanillin with a selection of amines. All the derivatives were characterized using 1H and 13C nuclear magnetic resonance and mass spectrometry. The vanillin derivatives were tested in several antioxidant assays with different mechanisms of action, in order to identify the functionalities that contributed to the antioxidant properties of this novel class of compounds. A structure-activity relationship (SAR) was therefore determined. The tetramer 4c turned out to be the most efficient antioxidant in all the assays. The latter compound consists of four vanillin moieties, together with a molecular structure that facilitates electron delocalisation for enhanced antioxidant activity. Selected based on their chemical structures and antioxidant properties, various vanillin derivatives were tested as potential multi-target-directed ligands (MTDLs), for use in the treatment of Alzheimer's disease (AD) - a multifactorial neurodegenerative disease. For this reason, the vanillin derivatives were tested for their ability to inhibit both the acetylcholinesterase (AChE) enzyme and the self-mediated A-beta(1-42) aggregation. The monomer 1f displayed the best inhibitory activities in both respects, with IC50 values at micro-M concentrations. In silico studies were performed in order to identify the molecular elements involved in the AChE inhibitory activities and to predict the ability of selected compounds to cross the blood-brain-barrier (BBB), which is of critical importance when targeting neurodegenerative diseases. Monomer 1f was predicted to be able to cross the BBB. Following this - and this time selected based on their antioxidant and AChE and amyloid inhibitory activities - another group of vanillin derivatives was then tested in oxidative stress models, by applying hydrogen peroxide or a mixture of rotenone/oligomycin A as stressors, in a neuroblastoma SH-SY5Y cell line. Vanillin derivatives showed cellular protective effects, for example by increasing cell viability and reducing reactive oxygen species (ROS) production. However, they were unable to protect the cells' DNA from oxidative damage. Again, compound 4c displayed the most efficient protective effects at micromolar concentrations. Finally, in order to study the mechanism behind the protective effects of 4c in SH-SY5Y cell line, research focused on its ability to activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, which is known to be a predominant mediator of cellular antioxidant response. Since no Nrf2 was observed in the nucleus, this confirms that there must be an alternative mechanism for the antioxidant activity of 4c. Overall, compounds 1f and 4c showed promise for their further development with the potential to assist in the treatment of AD

Mapping diffusion of Environmental Product Declarations released by European program operators

In order to facilitate the adoption of green requirements in public procurement, European Commission has developed the Green Public Procurement (GPP) criteria for various typologies of products and services. Almost all GPP criteria require environmental labels as means of proof that the goods or supplies correspond to the required environmental characteristics. Among the labels required, there are type III labels, based on a life cycle assessment study. The aim of this study is to (i) investigate to what extent a specific type III label, called Environmental Product Declaration (EPD), is spread in Europe and (ii) explore whether there is a correspondence between institutional initiatives towards GPP and the market. This study explored the valid EPDs presented on the websites of the European program operators between September and December 2016. The identified EPDs were quantified and classified according to the programme operator, title of the reference Product Category Rule (PCR), country, language and the product based on a classification system developed by the United Nations. In total, 4,888 EPDs were collected mainly released by the Institut Baum und Umwelt e.V. (IBU) and PEP ecopassport (PEP). The obtained results showed that countries with the greater number of EPDs are France and Germany and that construction products are the types of products labelled most. The analysis of the languages used in the EPDs showed that 45% of the identified EPDs are written in local languages. The obtained results have been cross-referenced with the national situations in terms of presence of National Action Plans (NAPs) and mandatory rules regarding GPP. Our analysis revealed that there is correspondence between the presence of a NAP with principles towards GPP and the spread in the market of environmental labelling and that the product sectors covered by EPDs correspond to the sectors covered by GPP criteria

Novel vanillin derivatives: synthesis, anti-oxidant, DNA and cellular protection properties.

Antioxidants have been the subject of intense research interest mainly due to their beneficial properties associated with human health and wellbeing. Phenolic molecules, such as naturally occurring Resveratrol and Vanillin, are well known for their anti-oxidant properties, providing a starting point for the development of new antioxidants. Here we report, for the first time, the synthesis of a number of new vanillin through the reductive amination reaction between vanillin and a selection of amines. All the compounds synthesised, exhibited strong antioxidant properties in DPPH, FRAP and ORAC assays, with compounds 1b and 2c being the most active. The latter also demonstrated the ability to protect plasmid DNA from oxidative damage in the presence of the radical initiator AAPH. At cellular level, neuroblastoma SH-SY5Y cells were protected from oxidative damage (H2O2, 400 mM) with both 1b and 2c. The presence of a tertiary amino group, along with the number of vanillin moieties in the molecule contribute for the antioxidant activity. Furthermore, the delocalization of the electron pair of the nitrogen and the presence of an electron donating substituent to enhance the antioxidant properties of this new class of compounds. In our opinion, vanillin derivatives 1b and 2c described in this work can provide a viable platform for the development of antioxidant based therapeutics

Synthesis of novel vanillin derivatives: novel multi-targeted scaffold ligands against Alzheimer's disease.

Alzheimer’s Disease (AD) is the most common cause of dementia worldwide, normally affecting people aged over 65. Due to the multifactorial nature of this disease, a “multi-target-directed ligands” (MTDLs) approach for the treatment of this illness has generated intense research interest in the past few years. Vanillin is a natural antioxidant and it provides a good starting point for the synthesis of new compounds with enhanced antioxidant properties, together with many biological activities, including ß-amyloid peptide aggregating and acetylcholinesterase inhibiting properties. Here we report novel vanillin derivatives, bearing a tacrine or a naphthalimido moiety. All compounds exhibited improved antioxidant properties using DPPH assay, with IC50 as low as 19.5 µM, FRAP and ORAC assays, with activities up to 1.54 and 6.4 Trolox equivalents, respectively. In addition, all compounds synthesized showed inhibitory activity toward acetylcholinesterase enzyme at µmolar concentrations using the Ellman assay. Computational docking studies of selected compounds showed interactions with both the catalytic anionic site and the peripheral anionic site of the enzyme. Furthermore, these compounds inhibited Aβ(1-42) amyloid aggregation using the fluorometric ThT assay, with compound 4 showing comparable inhibitory activity to the positive control, curcumin. At cellular level compound 4 (1 µM)showed significant protective effects of neuroblastoma SH-SY5Y cell line when treated with hydrogen peroxide (400 µM). In our opinion, vanillin derivatives could provide a viable platform for future development of multi-targeted ligands against AD

Intelligibility Assessment in Children with Cleft Lip and Palate in Italian and

Current research has shown that the speech intelligibility in children with cleft lip and palate (CLP) can be estimated automatically using speech recognition methods. On German CLP data high and significant correlations between human ratings and the recognition accuracy of a speech recognition system were already reported. In this paper we investigate whether the approach is also suitable for other languages. Therefore, we compare the correlations obtained on German data with the correlations on Italian data. A high and significant correlation (r=0.76; p<0.01) was identified on the Italian data. These results do not differ significantly from the results on German data (p>0.05). Index Terms: speech recognition, speech intelligibility, clef