Disclosing novel melanogenesis pathways: Formation of unexpected biphenyl-type dimers through radical–radical coupling by solid-state oxidation of the melanin biosynthetic precursor 5,6-dihydroxyindole

• Published in: Bioorganic chemistry 2024-12, Vol.153, p.107928, Article 107928
• Main Authors: Viggiano, Sara, Alfieri, Maria Laura, Panzella, Lucia, Crescenzi, Orlando, Napolitano, Alessandra
• Format: Article
• Language: English
• Subjects: 5,6-dihydroxyindole; Biphenyl Compounds - antagonists & inhibitors; Biphenyl Compounds - chemistry; Density functional theory; Dimerization; Free Radicals - chemistry; Free Radicals - metabolism; Indoles - chemical synthesis; Indoles - chemistry; Mechanochemistry; Melanin pigments; Melanins - biosynthesis; Melanins - chemistry; Melanins - metabolism; Melanogenesis; Molecular Structure; Oxidation-Reduction; Oxidative polymerization; Radical coupling; Solid-state reaction
• ISSN: 0045-2068; 1090-2120; 1090-2120
• DOI: 10.1016/j.bioorg.2024.107928

[Display omitted] •5,6-Dihydroxyindole solid-state oxidation chemistry was explored.•New biphenyl-type dimers were isolated and characterized.•Relevance to in vivo melanogenesis was demonstrated by ad hoc experiments.•New insights into the melanogenesis pathway are provided.•Access to melanin-related materials with hitherto unknown functional properties was gained. Investigation of the oxidation pathway of 5,6-dihydroxyindole (DHI), one of the main biosynthetic precursors of the brown-to-black skin and hair melanin pigments, represents a promising approach for the elucidation of the structure of these pigments in biological systems. We report herein the exploration of DHI oxidation chemistry under conditions so far poorly investigated, i.e. solid-state mechanochemical conditions, mimicking those that could be found in vivo in melanosomes, where melanin growth takes place in a confined space on a solid proteinaceous matrix, that allowed for the isolation and characterization of new dimers. Mechanistic experiments allowed to propose radical–radical coupling as the main dimerization pathway under solid-state conditions preventing ionic polymerization of the 5,6-dihydroxyindole system, indicating that the oxidation chemistry of this melanogenic precursor strongly depends on the reaction environment. The relevance for melanogenesis of the DHI oxidation pathway, disclosed herein, was also demonstrated by ad hoc experiments in which the solid-state reaction was carried out in the presence of proteins. Finally, the chromophores of the species generated by oxidation of the new dimers were investigated with a view to expanding the knowledge on the functional properties of melanin pigments, including mainly photoprotection.