Metallocorroles for photodynamic therapy and bioimaging

Hem, det røde fargestoffet i blod, har en lang rekke biologiske funksjoner. Molekylet består av en ytre ring laget av karbon og nitrogen, som omgir et jernatom. I syntetiske analoger har vi både endret strukturen til ringen og erstattet jern med andre metaller, spesielt palladium, platina og rhenium. De resulterende molekylene viste seg å være fosforescerende. Med andre ord, oppnår disse molekylene under belysning en langvarig eksitert tilstand, som enten kan utstråle sin ekstra energi (såkalt fosforescens) eller overføre den til oksygen (O2) og dermed frembringe såkalt singlet oksygen, en svært reaktiv form av oksygen som dreper levende celler. Disse molekylene lokaliseres også naturlig i kreftceller, og gir nye reagenser for fotodynamisk terapi. Disse funnene har blitt hyllet som et viktig bidrag fra det internasjonale kjemimiljøet, noe som førte til at PI ble tildelt Hans Fischer Career-prisen for livstidsprestasjoner i porfyrinkjemi, samt valgt inn i European Academy of Sciences. For en semipopulær beretning om korroler, se: Ghosh, A. Corrole and squeezed coordination. Nat. Chem. 2022, 14, 1474-1474; https://www.nature.com/articles/s41557-022-01096-8.

(1) Enormous progress has been made in the development of 5d metallocorrole sensitizers for photodynamic therapy and the oxygen sensing in tumors. Approximately 10 new classes of compounds have been developed, including about 100 individual compounds, of which about 50 have been crystallographically characterized. These include but are not limited to new rhenium, osmium, iridium, and gold corroles. (2) In the area of technetium chemistry, we have identified a [3 + 2] cycloaddition reaction that is specific to Tc and does not occur for Re, a discovery of great relevance to the development of SPECT imaging agents. (3) Substantial progress has also been made in the synthesis of expanded porphyrinoids, which promise strong two-photon absorption; these serve as the basis of a new grant application. In partial recognition of these findings, the PI has received the Hans Fischer Career Award for lifetime achievment in porphyrin chemistry and also been elected to European Academy of Sciences. The PhD student Rune Einrem is scheduled to defend his PhD in February, 2023, and has accepted a high-level industrial position in Norwegian industry. PhD scientist Dr. Abraham Alemayehu currently occupies a longer-term researcher position at UiT.

The present project builds on the recent synthesis in our laboratory of a unique family of 'size-mismatched complexes' - the 5d metallocorroles - where a large 5d transition metal is coordinated by a sterically constrained corrole ligand. The complexes exhibit room-temperature near-IR phosphorescence (lambda-max ~ 800 nm) with long triplet-state lifetimes (~ 100 microsecond). Early experiments furthermore indicate that the compounds may be used for optical O2 sensing under physiological conditions, highly efficient sensitization of singlet oxygen, triplet-triplet annihilation-based upconversion, and photodynamic therapy. Goal 1 of this project is to establish structure-property relationships vis-a-vis these applications and in particular to develop red/near-IR-absorbing sensitizers for photodynamic therapy of deep-seated tumors. A second line of research will involve p-block corroles involving boron, aluminum, gallium, silicon, germanium, and phosphorus. Some of these are known from the literature; others have been synthesized in our laboratory, partly in collaboration with Professor Penny Brothers of The University of Auckland, New Zealand. Many of these complexes are highly fluorescent and preliminary experiments indicate that at least a few also exhibit strong two-photon absorption. Goal 2 of this project will be to establish structure-property relationships for bioimaging and develop new amphiphilic p-block corrole derivatives as dyes for the increasingly important field of two-photon microscopy. As part of Goal 3 of this project, we will examine the possible synthesis and development of 99mTc-corrole radiopharmaceuticals, in collaboration with Professor Roger Alberto of the University of Zurich. Key groundwork, including successful syntheses of 99Tc corroles, is already in place for pursuing this objective.