Pyrrole-based Photosensitisers for Photomedicine. Synthesis, Photophysical and Photobiological Evaluation of Chlorins and Dipyrrin Complexes

Abstract

Photodynamic therapy (PDT) is a light activated therapy which involves a drug-photosensitiser (PS), light, and molecular oxygen. First, the PS is administered via a systemic or topical route and then it accumulates in the target lesion. The therapeutic effect is associated with the ability of the PS to generate its triplet excited state configuration upon excitation. This state can react with the coexisting molecular oxygen and trigger the production of highly reactive singlet oxygen (1O2) and other reactive oxygen species (ROS). These species result in a specific cell death of malignant cells or an antimicrobial effect against bacteria or viruses. The current clinically approved PSs for anti-cancer PDT are mainly porphyrinoids (e.g., Foscan, Tookad Soluble) and still encounter limitations (e.g., poor water solubility, aggregation, photobleaching, slow clearance from the body, etc.); therefore, it is important to discover alternative PSs. In this thesis, the development of novel pyrrole-based PSs was envisioned. First, chlorins which bear a gem-dimethyl group were synthesised and investigated for their in-vitro phototoxicity. The results showed that the chlorins can be potential PS candidates for PDT, given that they display very good phototoxicity against the colon carcinoma cell line CT26, high singlet oxygen quantum yields in polar solvents, modest fluorescence quantum yields and moderate triplet state lifetimes upon photoexcitation. Second, one of the zinc(II) chlorins underwent standard palladium catalysed cross-coupling reactions with various porphyrin units, resulting in the development of novel porphyrin-chlorin 1,4-phenylene linked arrays. Their excited state properties, their singlet oxygen generation and the in vitro studies shed light on the processes occurring upon photoexcitation. Porphyrin-chlorin arrays resulted in moderate fluorescence quantum yields and triplet excited lifetimes. In addition, they undergo fast energy transfer from the porphyrin to chlorin subunit and high singlet oxygen quantum yields were determined. However, the preliminary in vitro studies were not promising as due to their low permeability and high molecular weight they did not internalise in cells. Third, a library of novel aluminium(III) coordinated dipyrrin-based complexes was developed. The focus was given towards their photophysical and photobiological properties in order to elucidate their photodynamic efficacy. The tris(dipyrrinato)aluminium(III) chelates form excitonic states in their absorption spectra and are weakly fluorescence emitters. They displayed short-lived singlet excited states; however, they are accompanied by long-lived triplet excited states, and they moderately generate singlet oxygen upon irradiation. The properties are dependent by the environment polarity. The in vitro phototoxicity studies deemed half of the complexes as promising PDT agents since they exhibited great phototoxicity at low and safe concentrations. Time-dependent density functional theory calculations and single-crystal X-ray analysis were complementary assessed.