Diazirine linkers, such as trifluoromethyl phenyl DAs and alkyl DAs, generate reactive carbene species via loss of N2 upon photoirradiation at 350 nm. This active carbene easily inserts into neighboring C–H or heteroatom–H bonds and forms a covalent adduct. Additionally, the generated carbene has a quick half-life in the nanosecond range.
Diazirine linkers have emerged as a crucial tool in pharmaceutical research and development due to their ability to covalently link small molecules to their binding partners in a photo-activated manner. These linkers are characterized by a three-membered diazirine ring that undergoes ring-opening upon exposure to ultraviolet (UV) light, leading to the formation of a highly reactive carbene intermediate. This carbene intermediate can then react with neighboring molecules, enabling the covalent attachment of the small molecule to its binding partner.
Diazirine linkers have found widespread use in drug discovery, as they allow for the identification of protein targets of small molecules through photoaffinity labeling. This technique involves the covalent attachment of a diazirine-containing small molecule to its target protein, followed by UV irradiation to form a covalent bond between the two molecules. This enables the identification and isolation of the protein target, which can then be further characterized and studied.
Furthermore, diazirine linkers have been employed in the development of novel therapeutics, including photoactivatable prodrugs, which are designed to release their active pharmaceutical ingredient upon exposure to UV light. Additionally, diazirine linkers have been used in the design of photoresponsive biomaterials, which can undergo controlled changes in structure and function upon exposure to light.