This PhD thesis was elaborated under the joint supervision of Prof. Stefano Manfredini University of Ferrara, Dip. di Scienze della Vita e Biotecnologie, and Dr. Daniele Andreotti VP, Head of Medicinal Chemistry II at Aptuit, an Evotec company based in Verona, Italy. The spectrum of ultraviolet (UV) radiation is the major component of solar radiation, and it is associated with a multitude of effects on the skin (skin cancer and many other skin diseases such as tumors and premature photo-aging). In order to provide protection from the deleterious effects of solar radiation, especially the UV component (UV A/B), various measures have been adopted since time immemorial. Besides the use of physical protective measures, such as protective clothing and shields, various medicinal preparations which provide a barrier between the sun and the skin have been in use in the form of sunscreens. Of late, a new trend has emerged wherein an antioxidant preparation is employed to supplement the body’s antioxidant defence system in order to cope with the oxidative damage induced by solar radiation. The main goals of a sunscreen are to protect against UVB radiation and long-wavelength UVA radiation, to act as a reactive oxygen species (ROS) scavenger, and consequently to prevent damage to cells and DNA. So, with this purpose in mind the aim of my project is to design and synthesize compounds with dual capabilities, that filter broadly against UV A/B radiation and display antioxidant activity. The first approach explored was to use the commercial sunscreen PBSA (2-phenyl-1H-benzimidazole-5-sulfonic acid) as starting point. PBSA provides good protection against UVB rays but lacks filtering capacity for UVA radiation and it is devoid of antioxidant activity. Accordingly, 3 classes of derivatives, benzothiazoles, imidazopyrimidines and purines, were obtained via isosteric modification of PBSA. This last series of purine derivates required a completely different synthetic approach, which will be described in detail. Synthesized compounds were evaluated for their UV-filter and antioxidant activity. The best compound identified from the purine series was N0256-27-1, which features a high SPF and good antioxidant activity. In the second part of my thesis I will introduce the second starting point, Tinosorb S (bis-ethylhexyloxyphenol methoxyphenyl triazine) a photo-stable broad-spectrum UV filter. Again, my interest was in developing new derivatives to get a dual acting compound: broad filter UV A/B and antioxidant. To achieve this aim I proposed different chemical modifications of Tinosorb S, based on the scientific literature. The photoprotective capacity was determined using a spectrophotometric transmittance technique, whereas 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and Ferric Reducing Antioxidant Power (FRAP) assays were performed to determine antioxidant activity. Among the Tinosorb S derivatives, compound N0256-39-1 was found to offer the desired multifunctional profile to be considered as a potential candidate for development as a sunscreen component.
Il mio lavoro di dottorato nasce da una collaborazione tra l’Universita’ di Ferrara e il centro ricerche Aptuit, (presso Verona) avendo come tutor rispettivamente il Prof. Stefano Manfredini e il Dr. Daniele Andreotti. I raggi UV (ultravioletto) sono responsabili della maggior parte degli effetti cutanei causati dal sole quali invecchiamento precoce, tumore della pelle, melanoma,etc. Esistone diversi strumenti per proteggersi durante l’esposizione dagli effetti dannosi di tali raggi UVA e UVB, come ad esempio l’utilizzo di cappelli, indumenti di fibre naturali, occhiali da sole, ma anche strumenti di tipo chimico come appunto l’utilizzo di filtri solari. I raggi UVB sono più energetici rispetto a quelli UVA e sono responsabili di eritemi solari e scottature. I raggi UVA hanno una maggiore lunghezza d’onda e riescono a penetrare nella pelle piu’ in profondità causando la produzione dei radicali liberi responsabili di alterazioni cellulari, sviluppo di tumori della pelle, fotoinvecchiamento, etc. Da una recente ricerca bibliografica si evince che negli ultimi anni si e’ diffuso l’approccio di incorporare nelle formulazioni solari o di includere nella dieta l’utilizzo di antiossidanti, che abbiano un effetto fotoprotettivo della cute prevenendo i danni causati dai radicali liberi (ROS, Reactin Oxygen Species), di cui i raggi UVA sono appunto la fonte. L’obiettivo del mio lavoro di ricerca e’ stato quello di sintetizzare molecule con una un’attivita dualistica, in cui la proprieta’ filtrante ad ampio spettro nei confronti dei raggi UVA-B fosse associata ad una capacita’ antiossidante. Il punto di partenza e’ stato il PBSA (acido 2-fenil-1H-benzimidazolo-5-solfonico), un filtro solare commerciale efficace contro i raggi UVB, che però non offre una protezione dai raggi UVA ed è completamente privo di attività antiossidante. Modificando isostericamente la sua struttura sono state ottenute tre differenti classi di derivati (benzo-tiazolo, imidazo-pirimidine e purine).In particolar modo la serie chimica delle purine ha richiesto un approccio sintetico completamente differente dalle altre due classi. Tutti i composti sintetizzati sono stati valutati per l’attivita’ antiossidante utilizzando come saggi il DPPH e il FRAP e per l’attivita’ filtrante ad ampio spettro utilizzando delle tecniche spettrofotometriche. Il composto N0256-27-1, appartenente alla classe delle purine, ha mostrato un interessante profilo dal punto di vista del SPF (Fattore di Protezione Solare) e della capacita’ antiossidante. Nella seconda parte del mio lavoro di dottorato mi sono occupata di introdurre ad un filtro commerciale ad ampio spettro, Tinosorb S, capacita’ antiossidante Il composto N0256-39-1, appartente a questa classe di derivati. ha mostrato il miglior profilo raggiunto durante il lavoro di dottorato e verra’ caratterizzato ulteriormente per un ulteriore sviluppo.
Design, Synthesis, Characterization and Investigation of Structure-Activity Relationships on Antioxidants and/or UV Filtering Properties of New Potential Sunscreen Molecules
SERRA, ELENA
2020
Abstract
This PhD thesis was elaborated under the joint supervision of Prof. Stefano Manfredini University of Ferrara, Dip. di Scienze della Vita e Biotecnologie, and Dr. Daniele Andreotti VP, Head of Medicinal Chemistry II at Aptuit, an Evotec company based in Verona, Italy. The spectrum of ultraviolet (UV) radiation is the major component of solar radiation, and it is associated with a multitude of effects on the skin (skin cancer and many other skin diseases such as tumors and premature photo-aging). In order to provide protection from the deleterious effects of solar radiation, especially the UV component (UV A/B), various measures have been adopted since time immemorial. Besides the use of physical protective measures, such as protective clothing and shields, various medicinal preparations which provide a barrier between the sun and the skin have been in use in the form of sunscreens. Of late, a new trend has emerged wherein an antioxidant preparation is employed to supplement the body’s antioxidant defence system in order to cope with the oxidative damage induced by solar radiation. The main goals of a sunscreen are to protect against UVB radiation and long-wavelength UVA radiation, to act as a reactive oxygen species (ROS) scavenger, and consequently to prevent damage to cells and DNA. So, with this purpose in mind the aim of my project is to design and synthesize compounds with dual capabilities, that filter broadly against UV A/B radiation and display antioxidant activity. The first approach explored was to use the commercial sunscreen PBSA (2-phenyl-1H-benzimidazole-5-sulfonic acid) as starting point. PBSA provides good protection against UVB rays but lacks filtering capacity for UVA radiation and it is devoid of antioxidant activity. Accordingly, 3 classes of derivatives, benzothiazoles, imidazopyrimidines and purines, were obtained via isosteric modification of PBSA. This last series of purine derivates required a completely different synthetic approach, which will be described in detail. Synthesized compounds were evaluated for their UV-filter and antioxidant activity. The best compound identified from the purine series was N0256-27-1, which features a high SPF and good antioxidant activity. In the second part of my thesis I will introduce the second starting point, Tinosorb S (bis-ethylhexyloxyphenol methoxyphenyl triazine) a photo-stable broad-spectrum UV filter. Again, my interest was in developing new derivatives to get a dual acting compound: broad filter UV A/B and antioxidant. To achieve this aim I proposed different chemical modifications of Tinosorb S, based on the scientific literature. The photoprotective capacity was determined using a spectrophotometric transmittance technique, whereas 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and Ferric Reducing Antioxidant Power (FRAP) assays were performed to determine antioxidant activity. Among the Tinosorb S derivatives, compound N0256-39-1 was found to offer the desired multifunctional profile to be considered as a potential candidate for development as a sunscreen component.File | Dimensione | Formato | |
---|---|---|---|
Elena_Serra_Tesi.pdf
Open Access dal 21/08/2021
Descrizione: tesi digitale
Tipologia:
Tesi di dottorato
Dimensione
4.05 MB
Formato
Adobe PDF
|
4.05 MB | Adobe PDF | Visualizza/Apri |
I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.