New photosensitisers for photodynamic therapy

Abstract

The Photodynamic Therapy (PDT) of cancer is a relatively new area of cancer research. It involves the use of tumour specific drugs that are non-toxic in the absence of light but, when irradiated, react either with oxygen to give the cytotoxic singlet oxygen or directly with biomolecules and so cause cell death. Clinical PDT currently relies on porphyrin based drugs that have deleterious side effects.
A range of novel triarylmethane dyes based on Victoria Blue, a class of cationic photosensitisers which show promise for PDT, have been synthesised via their leuco bases from novel and known derivatives of benzhydrol and of 1-naphthylamine. A new synthesis of derivatives of the latter has been successfully developed and the synthesis of other intermediates has been improved. In addition, two series of new analogues of Victoria Blue in which vinyl or ethynyl units are inserted between the central carbon atom and the naphthalene moiety have been prepared by a variety of new and established routes. The work also includes a novel 3-step synthesis of some 3,6-bis(dialkylamino)fluoren-9-ones and a study of their subsequent conversion into the corresponding dyes and related compounds. The synthesis of some previously unknown benzopyranyl derivatives of Malachite Green has also been achieved and that of known and new 2,3-dimethyl analogues of Malachite Green and Crystal Violet has been improved.
The UV-visible absorption spectra of these dyes have been recorded in acetic acid-water mixtures and their interpretation has provided a much better understanding of pen hindrance in tertiary 1-naphthylamines, the importance of which has been confirmed by 'H NMR spectroscopy. The steric and electronic effects of the naphthalene ring in the Victoria Blue series have been clarified. Compounds containing extended chromophores showed red shifts of 80 to 100 nm of their absorption band but no significant increase in their absorption coefficients when compared to the parent triarylmethane dyes. It is suggested that these red shifts have different origins.
Increased planarity in the fluorenyl analogues of Victoria Blue produced a significant red shift of the absorption, but led to the deconjugation of the unbridged naphthyl ring and thus to the reduced stability of the dye cation. The absorption spectra of the heterocycic derivatives are broadly in line with the theoretically derived parameters.