Photophysical tuning of palladium metalated linear tetrapyrroles as potential photochemotherapeutic agents
Date
2021
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
University of Delaware
Abstract
Photodynamic therapy (PDT) is a recently approved, relatively non-invasive cancer treatment that utilizes light and the generation of singlet oxygen (1O2) as a reactive species to cause localized cytotoxicity. PDT shows promise as an alternative chemotherapy due to its efficient treatment and minimal side effects due to the localizable nature of the procedure, Current photosensitizers being utilized, while effective, still suffer from drawbacks that require continued development of PDT candidates. To this end, the Rosenthal group has previously developed palladium metalated biladiene(DMBil) complexes that generate significant 1O2, Pd[DMBil1], and have shown remarkable efficient photocytotoxicity, Pd[DMBil1]-PEG750, when compared to commercial photosensitizers. While highly promising, these complexes do not absorb deep-penetrating light between 600 and 900 nm for optimal 1O2 generation and photodynamic treatment. Excessive bromination of the freebase DMBil and the parent Pd[DMBil1] complex, yields three new halogenated tetrapyrroles in DMBilBr10 and palladium(II) isocorroles Pd[ICBr6] and Pd[ICBr8]. The new freebase DMBilBr10 showed a significant red-shift In absorption out to 600 nm, while both isocorrole complexes showed impressive absorption deep in the phototherapeutic window. Both Pd[ICBr6] and Pd[ICBr8] display rich photochemical and electrochemical properties, but these properties do not appear to align for PDT to be the best application for these new complexes. During the optimization of synthesizing polyhalogenated target derivatives, it was discovered that the parent Pd[DMBil1] could be selectively halogenated yielding Pd[DMBilBr2]. This newly isolated Pd[DMBilBr2] was an optimal candidate for Sonogashira-coupling chemistry and was the starting material for a new suite of extended-conjugated palladium(II) biladienes (Pd[DMBil2-X]). The robust modification with varying aryl-alkyne groups yielded a variety of complexes with a range of electron-withdrawing and donating functionalization, Pd[DMBil2-CF3], Pd[DMBil2-tBu], and Pd[DMBil2-N(CH3)2] as examples. These Pd[DMBil2] complexes show promise for PDT after in-depth photophysical analysis that revealed absorptions past 600 nm and noticeable 1O2 generation from most derivatives. Photophysical characteristics such as molar absorptivity, absorption λmax, and 1O2 production, could also be tuned based on correlation with the electronic substitution on the aryl appendages. With a new series of Pd[DMBil2-X] in hand, a different approach towards functionalizing these photosensitizers for water-solubility was employed through nucleophilic attack using propargyl alkoxide. The resulting free alkyne(s) allowed for facile “click” chemistry to append polyethylene glycol chains to improve water-solubility of Pd[DMBil2]-diPEG750. A noticeable bathochromic shift was present once Pd[DMBil2]-diPEG750, give strong absorption within the phototherapeutic window and still maintain 1O2 production. The work presented, will demonstrate synthetic efforts and subsequent photochemical and electrochemical studies, to tune the photophysical properties of these tetrapyrroles for optimal use in PDT in the phototherapeutic window.
Description
Keywords
Palladium metalated linear tetrapyrroles, Photochemotherapeutic agents