Nichtsteroidale Antiandrogene natürlichen und synthetischen Ursprungs zur Behandlung des Prostatakarzinoms

Benign prostatic hyperplasia (BPH) afflicts over 40% of men aged 60 years or older and is closely related with the development of prostate cancer (PCa), which is the most commonly diagnosed malignancy and second leading cause of cancer death in men in Western countries. Both prostatic diseases are associated with an enlargement of the prostate. The growth of this organ is regulated by the male sexual hormones, the androgens. These bind to the AR, which transactivates target genes. Therefore the main target for the treatment of prostate enlargement, especially the malignant type PCa, is the down regulation of androgens realized by the use of antiandrogenic agents like the well-known nonsteroidal antiandrogen Flutamid (Fugerel®) for example. In the present study three plant species, which are traditionally used in the treatment of BPH, were tested for their antiandrogenic activity using the androgen receptor (AR) responsive MMTV-Luc reporter gene assay. From these three plant species Serenoa repens, Cucurbita pepo and Pygeum africanum, the latter showed the highest bioactivity and therefore selective extracts were made from the stem barks of Pygeum africanum. The resulting extracts of n-hexane, methylene chloride, methanol, methanol/water 50/50 and water were tested for their antiandrogenic properties and the selective methylene chloride extract showed the strongest effect and was therefore chosen for a bioactivity-directed fractionation, which was performed as a preparative gradientextrography. The resulting 35 fractions were tested for their antiandrogenic properties again and examined for their constituents by HPLC and after all, the substances benzoic acid, atraric acid and N-Butylbenzenesulfonamide (NBBS) were isolated from the active fractions. Atraric acid and NBBS revealed strong antiandrogenic activities in the MMTV-Luc reporter gene assay and were therefore chosen as leadstructures. The leadstructures were optimized by organic-preparative reactions. The synthesized fourteen sulfonamides and six atraric acid derivatives were tested together with several reference substances in order to get some information about an existing structure-activity relationship. Finally N-Butyl-4-nitro-3-trifluoromethylbenzenesulfonamide revealed the highest antiandrogenic activity, scilicet an inhibition of the androgen induced luciferase activity of 75% at a concentration of 1 µM. The leadstrucures were also analysed for their receptor binding specificity and the growth inhibition of LNCaP prostate cancer cells leading to the conclusion that NBBS and atraric acid both have a high affinity to the androgen receptor and only to some extent to the progesterone receptors A and B, while other steroid receptors were unaffected by these substances. Treatment of LNCaP cells with NBBS and atraric acid inhibited potently LNCaP proliferation.