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Osteoporosis is predominantly treated with drugs that inhibit further bone resorption due to estrogen deficiency. Yet, osteoporosis drugs that not only inhibit bone resorption but also stimulate bone formation, such as potentially inhibitors of 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2), may be more efficacious in the treatment of osteoporosis. Blockade of 17β-HSD2 is thought to increase intracellular estradiol and testosterone in bone, thereby inhibiting bone resorption by osteoclasts and stimulating bone formation by osteoblasts, respectively. We here describe the design, synthesis, and biological characterization of a novel bicyclic-substituted hydroxyphenylmethanone 17β-HSD2 inhibitor (compound 24). Compound 24is a nanomolar potent inhibitor of human 17β-HSD2 (IC50of 6.1 nM) and rodent 17β-HSD2 with low in vitro cellular toxicity, devoid of detectable estrogen receptor α affinity, displays high aqueous solubility and in vitro metabolic stability, and has an excellent oral pharmacokinetic profile for testing in a rat osteoporosis model. Administration of 24in a rat osteoporosis model demonstrates its bone-sparing efficacy.

Species of Aristolochiaare used as herbal medicines worldwide. They cause aristolochic acid nephropathy (AAN), a devastating disease associated with kidney failure and renal cancer. Aristolochic acids I and II (1and 2) are considered to be responsible for these nephrotoxic and carcinogenic effects. A wide range of other aristolochic acid analogues (AAAs) exist, and their implication in AAN may have been overlooked. An LC-MS- and 1H NMR-based metabolomic analysis was carried out on 43 medicinally used Aristolochiaspecies. The cytotoxicity and genotoxicity of 28 Aristolochiaextracts were measured in human kidney (HK-2) cells. Compounds 1and 2were found to be the most common AAAs. However, AA IV (3), aristolactam I (4), and aristolactam BI (5) were also widespread. No correlation was found between the amounts of 1or 2and extract cytotoxicity against HK-2 cells. The genotoxicity and cytotoxicity of the extracts could be linked to their contents of 5, AA D (8), and AA IIIa (10). These results undermine the assumption that 1and 2are exclusively responsible for the toxicity of Aristolochiaspecies. Other analogues are likely to contribute to their toxicity and need to be considered as nephrotoxic agents. These findings facilitate understanding of the nephrotoxic mechanisms of Aristolochiaand have significance for the regulation of herbal medicines.

Molecular and cellular effects of lifelong or even multigenerational exposure of phytoestrogens (PEs) are still controversially discussed and gain substantial public attention. While PE-rich diets may be preventive towards menopausal complications as well towards hormone dependent cancer formation, it seems as if late PE exposure at an advanced age results in increased risk of hormonal carcinogenesis in certain animal studies. Long-term epidemiological studies imply a protective effect of PEs on breast tissue as indicated by reduced rates of breast cancer in countries with high consumption of PE-rich soy products, as in Southeast Asia. Although, it is still speculative if the biological effects of soy products derive only from the contained PE. It is known for a number of endocrine modulating substances that the timing of exposure is a crucial element of its final effects. Therefore, exposure during critical developmental windows, such as the embryonal or fetal, the early postnatal and pubertal period, is most likely to have an important impact and result in longest-lasting effects. Thus, these effects may not only result from direct exposure to specific tissues but also by germline modifications. In summary, a number of new studies demonstrate that lifelong PE exposure is able to affect estrogen sensitive tissues, apparently in a tissue selective manner, effects which differ from later life exposure. With respect to health risks and benefits, these data indicates that the situation is much more complex then expected, and these results are highly relevant for the interpretation of regional differences in endocrine-related cancer incidence.

Tamoxifen is the most widely prescribed anti-neoplastic drug for the treatment of both localized and metastatic breast cancer. It is also the prototype for a class of drugs that are referred to as selective estrogen receptor modifiers (SERMs), most of which have both estrogenic and anti-estrogenic activity in estrogen target tissues including the breast and endometrium. The underlying mechanisms of action of SERMs in the breast and endometrium that lead to profound differences in the tissue-specific effects of tamoxifen have not yet been elucidated.We have compared the effects of tamoxifen and the pure anti-estrogen ICI 182,780 (Faslodex) in the RUCA-I hormone-responsive rat endometrial cell line in vitroand in vivo. In cell culture, RUCA-I cells responded to both estrogens and anti-estrogens, and the expression of clusterin and complement C3 mRNAs required the presence of estradiol and was repressed in the absence of estradiol or in the presence of the pure anti-estrogen ICI 182,780. Tamoxifen, on the other hand, induced both complement C3 and clusterin mRNA in the absence of estradiol and failed to repress their expression in the presence of estradiol. When grown as subcutaneous xenografts in syngeneic Da/Han rats for 5 weeks, the RUCA-I cells retained their sensitivity to estradiol, as demonstrated by significantly enhanced tumor growth in intact female rats compared with the growth in ovariectomized rats. But neither ICI 182,780 nor tamoxifen had a significant impact on tumor growth in cycling or ovariectomized animals. On the other hand, tamoxifen was potently estrogenic in metastatic lymph nodes, increasing the size of the lymph node tumors almost 6-fold over that seen in the intact cycling animals. In primary tumors, the expression of complement C3 mirrored that seen in vitro, although tamoxifen showed some agonist activity in ovariectomized animals. Tamoxifen also displayed marked agonist activity with respect to clusterin expression and enhanced clusterin mRNA levels and protein in both the primary tumors and lymph metastases in intact and ovariectomized animals.Given the recent demonstration that over-expression of clusterin increases the metastatic potential of breast cancer cells, these data may provide a mechanistic explanation for the increased incidence of endometrial cancer in postmenopausal patients treated with tamoxifen.

Phytoestrogene sind Inhaltsstoffe von Pflanzen, die mit estrogenabhängigen Signalkaskaden interagieren und ihre Wirkung bevorzugt über die Rezeptoren ER-α und ER-β ausüben. Werden nicht alle Wirkungen hervorgerufen, die auch durch Estradiol auszulösen sind, sondern organspezifische, mehr oder weniger selektive Wirkprofile stimuliert, so spricht man von einem “Selectiven Estrogen Receptor Modulator” (SERM). Dieser SERM-Begriff, angewandt auf Phytoestrogene, führt zur Klassifizierung einiger Phytoestrogene als Phyto-SERMs. Pflanzliche Inhaltsstoffe mit estrogener Aktivität weisen mehr oder weniger stark ausgeprägte SERM-Eigenschaften auf. Prinzipiell handelt es sich bei diesen “Phyto-SERMS” um pharmakologisch interessante Substanzen, die zwar schon z.T. klinisch genutzt werden, für die aber aus der Sicht Molekularer Endokrinologen durchaus noch ein mehr oder weniger stark ausgeprägter Bedarf zur weiteren Charakterisierung besteht.

Naturally occurring naringenin derivatives, known for their estrogenic activity, were tested in two independent (anti-)androgen screening assays. Using a yeast-based androgen receptor assay relatively strong antiandrogen activities were demonstrated for 6-(1,1-dimethylallyl)naringenin and 8-prenylnaringenin, while the parent compound naringenin did not show recognizable antiandrogen activity. In an androgen receptor activity assay based on the analysis of prostate specific antigen (PSA) concentrations in the supernatants of treated PC3(AR)2 cells the antiandrogenic activity of 6-(1,1-dimethylallyl)naringenin was detected at concentrations of 10 -5 M. 8-Prenylnaringenin or naringenin have no detectable antiandrogenic effect. In summary, for the first time we provide evidence of the antiandrogenic activity of 6-DMA-N in two independent model systems. In conclusion, we demonstrated the ability of prenylated naringenins not only to act via the estrogen receptor but also through the androgen receptor. Abbreviations. DHT:dihydrotestosterone PSA:prostate-specific antigen Bic:bicalutamide 6-DMA-N:6-(1,1-dimethylallyl)naringenin 8-P-N:8-prenylnaringenin E2:17-β estradiol