Synthesis, in vitro cellular uptake and photo-induced antiproliferative effects of lipophilic hypericin acid derivatives (original) (raw)

Bioorganic & Medicinal Chemistry, 2005

Abstract

Hypericin, a naturally occurring hydroxylated phenanthroperylene dione, is used as a powerful photosensitizer for photodynamic therapy as well as a diagnostic tool for the fluorescence detection of flat neoplastic lesions in the bladder of patients. Both applications are based on the tumouritropic characteristics of the compound. To get more insight into some of the physicochemical properties of hypericin affecting its tumouritropic characteristics, we set out to synthesize a series of more lipophilic hypericins. For this purpose, a synthetic pathway to hypericin acid amides with hydrocarbon chains of different lengths stably attached by an amide bond at position C10 was explored. Hypericin acid proved inert in amide forming reactions, whereas the precursor protohypericin acid showed higher reactivity and resulted in the desired amide derivatives, which afterwards can be easily converted into their phenanthroperylene dione form. Hexyl-, octyl-, decyl- and dodecylamides of hypericin acid were successfully synthesized in this way. In vitro cellular uptake and photo-induced antiproliferative effects of the compounds were evaluated, using the human moderately differentiated non-invasive papillary transitional carcinoma RT-112 cell line. Whereas the more lipophilic amides were taken up limitedly, the hexylamide accumulated approx. as well as hypericin itself. From the antiproliferative data it can further be concluded that not only the cellular uptake, but also the light-induced activity, is affected by the introduced structural changes.

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