Greco, Giorgia (2010) Synthesis and reactivity of phenolic systems conjugated with sulfidrylic compounds. [Tesi di dottorato] (Unpublished)

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Conjugates of phenols with biological thiols have recently received increasing interest because of their peculiar properties in most cases enhanced or significantly modified with respect to the parent phenols. Main focus of the research activity developed in this PhD work was the chemistry of thioalkyl conjugates of catechols, among these cysteinyldopas, mainly the 5S and 2S isomers, that are produced by epidermal melanocytes of man and other mammals and are involved in the biosynthesis of pheomelanins, the characteristic pigments of red hair, commonly implicated in the abnormal susceptibility of red haired fair complexioned individuals to sunburn and skin cancer. Overall the results of this work have greatly contributed to the definition of the structure, biosynthesis and functional significance of pheomelanins. Traditionally pheomelanins have been regarded to arise primarily via the oxidative polymerization of 5-S-cysteinyldopa (5SCD). Yet, it was observed that, in addition to 5SCD, 2-S-cysteinyldopa (2SCD) is an important building block of red human hair pigments. By an improved analytical procedure, allowing simultaneous determination of benzothiazole markers, BTCA and 2-BTCA, originating from oxidative degradation of 5SCD- and 2SCD-derived units respectively, evidence was obtained that the pigment suffers extensive degradation during hair growth affecting mainly the 5SCD-derived components, whereas the 2SCD-derived units remain largely unaffected. Model studies suggested that structural degradation occurs during hair growth probably as a result of oxidative processes related in part to sun exposure. Detailed studies on the properties of synthetic pheomelanin from 5SCD showed that the pigment is an efficient redox cycler, promoting oxygen-dependent polycatechol(amine) formation and deposition of eumelanin-like antioxidant coatings. Scanning electron microscopy coupled with chemical analysis of the material revealed a eumelanin-like coating completely masking the pheomelanin component. The system provides a new explanation to the origin of the casing architecture of human melanin. The benzothiazoles BTCA and 2-BTCA turned out to be important and selective markers for pheomelanin quantitation in tissues and identification of red-haired individuals at high risk for skin cancer. A straightforward synthetic procedure for large scale preparation of these compounds was developed which might allow their use for routine population screenings, and for genetic and epidemiologic correlations studies. The presence of benzothiazole compounds was also investigated in the urine of patients with melanoma with or without diffuse melanosis, a rare condition which may occur in metastasizing melanoma and is associated with a very poor prognosis. The urinary BTCAs were found to be highly associated with melanosis. Moreover, analysis of the pigmented fraction of urine after oxidative degradation provided evidence for the presence of pheomelanins at high levels in patients with melanosis. This finding provided for the first time a direct evidence that benzothiazoles are pheomelanin metabolites, whose formation is associated with advanced stages of melanoma. Due to the unfavourable chemical and physical properties of pheomelanins, their structure is still mainly unknown. Biomimetic oxidation of the pheomelanin precursor 5SCD led to the isolation of two unprecedented benzothiazolylthiazinodihydroisoquinoline dimers. Although the existence of isoquiniline-containing structural motifs in pheomelanins has long been postulated, this study was the first to demonstrate their presence in red hair and to uncover possible precursor compounds and formation mechanism. As part of studies on thiol-quinone coupling as a viable biomimetic access to novel bioactive compounds for practical applications, the reaction of dihydrolipoic acid (DHLA), a strong endogenous antioxidant, with p-naphtoquinones was examined, leading to the identification of novel dithiepines arising from ring expansion of an unstable spirocyclic dithiane. In addition new conjugates of DHLA with naturally occurring polyphenols, such as hydroxytyrosol, caffeic acid and piceatannol, were prepared, which showed higher antioxidant power than the parent catechol, as evidenced by the higher H-donating ability and the tendency to oxidation at physiological pHs.

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