Lead structures for applications in photodynamic therapy. Part 1: Synthesis and variation of m-THPC (Temoporfin) related amphiphilic A2BC-type porphyrins

Photodynamic therapy (PDT) is a developing modality for the treatment of certain tumorous and other diseases. Considerable progress has been made in recent years in the search for new photosensitizers, in particular elucidating the role of localization of the photosensitizer. Known successful photosensitizers of the tetrapyrrole type are amphiphilic molecules, preferably localizing in cellular membrane structures. Thus, the quest for new photosensitizers requires the synthesis of unsymmetrically substituted (amphiphilic) tetrapyrroles. In this article, we describe strategies for the de novo synthesis of amphiphilic tetrapyrroles using a 3-hydroxyphenyl substituted tetrapyrrolic system (Temoporfin) as the lead structure. From an applied science-oriented approach, such a set of amphiphilic porphyrins is best synthesized by combining well-developed condensation methods with subsequent functionalization via organolithium compounds or transition metal catalyzed coupling protocols. Starting from simple A2- or AB-porphyrins, the synthesis of A2B-, A3-, A3B-, and A2BC-porphyrins with a mixed hydrophilic/hydrophobic substitution pattern is described. Because of the versatility of this approach to unsymmetrically substituted porphyrins it is also applicable to other areas where porphyryns with a tailor-made substitution patterns are needed, for example, catalysts or molecular electronic devices based on tetrapyrroles.