The highest incidence of melanoma in red haired individuals is attributed to the synthesis and phototoxic properties of pheomelanin pigments. Recently, pheomelanin has also been implicated in UV-independent pathways of oxidative stress; however, the underlying mechanisms have remained uncharted. Herein, we disclose the unprecedented property of purified red human hair pheomelanin (RHP) to promote (i) the oxygen-dependent depletion of major cell antioxidants, for example glutathione and NADH; (ii) the autoxidative formation of melanin pigments from their precursors. RHP would thus behave as a unique 'living' polymer and biocatalyst that may grow by simple exposure to monomer building blocks and may trigger autoxidative processes. These results yield new clues as to the origin of the pro-oxidant state in the red hair phenotype, uncover non-enzymatic pathways of melanogenesis, and pave the way to innovative strategies for melanoma prevention.

Nature provides a primary source of leads for the design of π-conjugated organic chromophores and other functional molecular systems useful for molecular recognition, light harvesting, photoconversion, and other technological applications. In this Account, we draw attention to a unique group of naturally occurring heterocyclic compounds, the 2H-1,4-benzothiazines and related benzothiazole derivatives. Derived from tyrosine and cysteine, these molecules arise from a mutation-induced deviation of the melanin pathway to provide the core structure of the red human hair pigments pheomelanins. Since the elucidation of the biosynthetic pathway of pheomelanins in the 1960s, researchers have focused on 1,4-benzothiazines and red hair pigments. Not only do these molecules have interesting photochemical and molecular recognition properties, they also have compelling biomedical significance. Numerous studies have linked higher levels of pheomelanins and mutations in the pathways that produce these pigments in individuals with red hair and fair skin with an increased sensitivity to UV light and a higher susceptibility to melanoma and other skin cancers. Prompted by new data about the structure and photochemistry of the bibenzothiazine system, this Account highlights the chemistry of benzothiazines in red-haired individuals as a novel source of inspiration in the quest for innovative scaffolds and biomimetic functional systems. Model studies have gradually shed light on a number of remarkable physical and chemical properties of benzothiazine-based systems. Bibenzothiazine is a robust visible chromophore that combines photochromism and acidichromism. Benzothiazine-based polymers (synthetic pheomelanins) show remarkable photochemical, paramagnetic, and redox cycling properties. Biomimetic or synthetic manipulations of the benzothiazine systems, through decarboxylation pathways controlled by metal ions or unusually facile ring-contraction processes, can produce a diverse set of molecular scaffolds.

In the presence of micromolar peroxides or biometals (Fe(III), Cu(II), V(V) salts), and following a strong acid input, the stable 3-phenyl-2H-1,4-benzothiazine is efficiently converted to a green-blue Δ(2,2')-bi(2H-1,4-benzothiazine) chromophore via dehydrogenative coupling of a 1,4-benzothiazinyl radical. The new system is of potential practical interest for colorimetric peroxide and redox biometal detection.

A current challenge in medical diagnostics is how to obtain high MRI relaxation enhancement using Gd^III-based contrast agents (CAs) containing the minimum concentration of GdIII ion. We report that in...

Symmetrical glycosyl disulfides can be prepared within a few hours from per-O-acetylated precursors via a sequential approach entailing short reactions and no purification of any intermediate. The final thiolate-to-disulfide oxidation step is noticeably accelerated by low amounts of phenyl diselenide under air. Applicability of the strategy to non-saccharidic symmetrical alkyl disulfides has also been examined. A preliminary assay of the cytotoxic activity of symmetrical 1,1'- disulfides was performed on two human tumor cell lines, and a noteworthy activity was recorded for a range of these synthetic compounds.