Photodynamically Active Hypericin Derivatives

Hypericin is a natural organic product which occurs in a variety of organisms. Its sedative, anti-viral and photodynamic potential is presently mined for a variety of medicinal applications. The most important field of hypericin applications seems presently to be that of photodynamic therapy where it is used an an anti-viral agent to destroy virus particles in blood preparations or to sensitize the destruction of topical tumors. With respect to its applications in photodynamic therapy, it has a main drawback because its long wavelength absorption band at about 590 nm lays outside the range of most medicinal lasers, which commonly emit in the range of 650 nm. Therefore the aim of this project is the modification of hypericin in a way to red-shift the absorption band into the range of typically used medicinal lasers, but leaving its photodynamic activities untouched. Over the last years some efforts were made to reach this goal but unfortunately no modification, which provides both (red shift and photodynamic activity) was found. To avoid the problems that occurred in the past, the functionalization of the positions 9 and 12 of the hypericine skeleton should be useful. These positions are far from the strategic bay sites of the molecule (which are important for the photosensitizing activities of hypericine). Preliminary MO calculations showed, that the introduction of carbonyl groups in this positions could be a promising way to realize the above mentioned bathochromic shift. As long as hypericine itself can hardly be derivatised, we intend to start with the natural product emodin on which we will try to introduce different (bathochromic shifting) substituents and then to dimerize it to the corresponding hypericin derivatives. All novel derivatives would have to be properly characterized by their spectroscopic and static photophysical properties. Finally it has to be said, that photodynamically active substances are of great interest in the medical research for potentially anti tumor agents. Therefore new, red-shifted hypericin derivatives which absorb in the typical range of commonly used medicinal lasers could be of interest in this field of medicinal research and applications.

Cancer and retroviruses (like HIV) are two severe problems in our society nowadays. Accordingly, there is an increasing interest in the development of new drugs and new therapeutic methods. One quite promising chemotherapeutic method for the treatment of several cancers is the photodynamic therapy (PDT), which involves the use of a photosensitizer, which upon illumination destroys the virus. Among the potential photosensitizers known, hypericin is one of the most promising ones, also possessing potential antiviral activity. Unfortunately, the applicability of hypericin in PDT suffers from an absorption maximum (max = 590-600 nm) lying outside the optimum wavelength range (max = 620-800 nm) for a photosensitizer used together with medical lasers. Thus, several promising new hypericin derivatives (second generation hypericin based photosensitizers) have been reported over the last years. The aim of this project was to investigate the selective functionalization of hypericin in positions 9 and 12, which have not been accessible so far. First, the main focus was on the introduction of carbonyl groups in the intended positions starting from the hypericin precursor emodin. Carbonyl groups were supposed to be promising substituents as they might lead to a bathochromically shifted absorption maximum of the hypericin moiety, which is of main interest in the research for second generation hypericin based photosensitizers. In addition, carbonyl groups are very useful for further conjugation and substitution reactions. We have shown, that syntheses of bathochromically shifted, 9,12-dicarbonyl substituted hypericin derivatives are possible via intramolecular Friedel- Crafts acylations. Furthermore, several promising 7-carbonyl and 7-carboxyl substituted emodin derivatives could be obtained. The applicability of the novel, 7-carbonyl substituted emodin derivative for a study concerning the photochemical properties of heterocyclically disubstituted hypericin derivatives with respect to the substitution site was shown. It was found that these properties mainly differ with respect to the substitution site. Finally, investigations concerning the bifunctionalization of emodin in positions 6 and 7 with respect to the synthesis of a new class of heterocyclically fused hypericin derivatives were undertaken. It was found, that syntheses of such generally difficultly available anthraquinone derivatives are possible with a modified Marschalk type reaction as the key step. The novel pyridazinone fused hypericin derivative described, possessed a satisfying bathochromically shifted absorption maximum making it a promising candidate for further investigations concerning a possible application in photodynamic therapy. Furthermore, the herein described strategy for the bifunctionalization of emodin provided a novel route for the syntheses of such difficultly available anthraquinone derivatives.