Organometallic gold(iii) complexes with hybrid SNS-donating thiosemicarbazone ligands: cytotoxicity and anti-Trypanosoma cruzi activity.

Stable organogold(iii) compounds of the composition [AuIII(Hdamp)(L1)]Cl are formed from reactions of [AuCl2(damp)] with H2L1 (damp- = dimethylaminomethylphenyl; H2L1 = N'-(diethylcarbamothioyl)benzimidothiosemicarbazides). The cationic complexes can be neutralized by reactions with weak bases under the formation of [AuIII(damp)(L1)] compounds. The structures of the products show interesting features like relatively short AuH contacts between the methylene protons of the Hdamp ligand and the gold(iii) ions. Preliminary biological studies on the uncoordinated compounds H2L1 and their gold complexes indicate considerable cytotoxicity for the [AuIII(Hdamp)(L1)]Cl complexes against MCF-7 cells. The in vitro trypanocidal activity was evaluated against the intracellular form of Trypanosoma cruzi. The organometallic complexes display a remarkable activity, which is dependent on the alkyl substituents of the thiosemicarbazone building blocks of the ligands. One representative of the cationic [AuIII(Hdamp)(L1)]Cl complexes, where H2L1 contains a dimethylthiosemicarbazide building block, shows a trypanocidal activity against the intracellular amastigote form in the same order of magnitude as that of the standard drug benznidazole. Furthermore, no appreciable toxicity to mice spleen cells is observed for this compound resulting in a therapeutic index of about 30, which strongly recommends it as a promising candidate for the development of a future antiparasitic drug.

Evaluation of selected 3D virtual screening tools for the prospective identification of peroxisome proliferator-activated receptor (PPAR) γ partial agonists.

The peroxisome proliferator-activated receptor (PPAR) γ regulates the expression of genes involved in adipogenesis, lipid homeostasis, and glucose metabolism, making it a valuable drug target. However, full activation of the nuclear receptor is associated with unwanted side effects. Research therefore focuses on the discovery of novel partial agonists, which show a distinct protein-ligand interaction pattern compared to full agonists. Within this study, we employed pharmacophore- and shape-based virtual screening and docking independently and in parallel for the identification of novel PPARγ ligands. The ten top-ranked hits retrieved with every method were further investigated with external in silico bioactivity profiling tools. Subsequent biological testing not only confirmed the binding of nine out of the 29 selected test compounds, but enabled the direct comparison of the method performances in a prospective manner. Although all three methods successfully identified novel ligands, they varied in the numbers of active compounds ranked among the top-ten in the virtual hit list. In addition, these compounds were in most cases exclusively predicted as active by the method which initially identified them. This suggests, that the applied programs and methods are highly complementary and cover a distinct chemical space of PPARγ ligands. Further analyses revealed that eight out of the nine active molecules represent novel chemical scaffolds for PPARγ, which can serve as promising starting points for further chemical optimization. In addition, two novel compounds, identified with docking, proved to be partial agonists in the experimental testing.

Antiglioma activity of GoPI-sugar, a novel gold(I)-phosphole inhibitor: chemical synthesis, mechanistic studies, and effectiveness in vivo.

Glioblastoma, an aggressive brain tumor, has a poor prognosis and a high risk of recurrence. An improved chemotherapeutic approach is required to complement radiation therapy. Gold(I) complexes bearing phosphole ligands are promising agents in the treatment of cancer and disturb the redox balance and proliferation of cancer cells by inhibiting disulfide reductases. Here, we report on the antitumor properties of the gold(I) complex 1-phenyl-bis(2-pyridyl)phosphole gold chloride thio-ß-d-glucose tetraacetate (GoPI-sugar), which exhibits antiproliferative effects on human (NCH82, NCH89) and rat (C6) glioma cell lines. Compared to carmustine (BCNU), an established nitrosourea compound for the treatment of glioblastomas that inhibits the proliferation of these glioma cell lines with an IC50 of 430µM, GoPI-sugar is more effective by two orders of magnitude. Moreover, GoPI-sugar inhibits malignant glioma growth in vivo in a C6 glioma rat model and significantly reduces tumor volume while being well tolerated. Both the gold(I) chloro- and thiosugar-substituted phospholes interact with DNA albeit more weakly for the latter. Furthermore, GoPI-sugar irreversibly and potently inhibits thioredoxin reductase (IC50 4.3nM) and human glutathione reductase (IC50 88.5nM). However, treatment with GoPI-sugar did not significantly alter redox parameters in the brain tissue of treated animals. This might be due to compensatory upregulation of redox-related enzymes but might also indicate that the antiproliferative effects of GoPI-sugar in vivo are rather based on DNA interaction and inhibition of topoisomerase I than on the disturbance of redox equilibrium. Since GoPI-sugar is highly effective against glioblastomas and well tolerated, it represents a most promising lead for drug development. This article is part of a Special Issue entitled: Thiol-Based Redox Processes.

A liberal preoperative fasting regimen improves patient comfort and satisfaction with anesthesia care in day-stay minor surgery.

BACKGROUND: The aim of this study was to evaluate whether a single preoperative limited oral intake of a carbohydrate drink could improve perioperative patient comfort and satisfaction with anesthesia care in elective day-stay ophthalmologic surgery. METHODS: A single-center, prospective, randomized clinical trial was conducted in a university hospital. The study included ASA I-III patients undergoing ophthalmologic surgery. Patients undergoing both general anesthesia and local anesthesia were included in the study. The control group fasted in accordance to nil per os after midnight, while patients in the experimental group received 200 mL of a carbohydrate drink 2 h before the operation. Both groups were allowed to drink and eat until midnight ad libitum. Patient characteristics, subjective perceptions, taste of the drink, and satisfaction with anesthesia care were ascertained using a questionnaire administered three times: after the anesthesiologist's visit, before surgery and before discharge from the ward to assess patient comfort. An analysis of variance and the Mann-Whitney U-test were used for statistical analysis. RESULTS: A total of 123 patients were included and 109 patients were randomly assigned to one of two preoperative fasting regimens. Patients drinking 200 mL 2 h before surgery were not as hungry (P<0.05), not as thirsty preoperatively (P<0.001) and not as thirsty after surgery (P<0.05), resulting in increased postoperative satisfaction with anesthesia care (P<0.05). CONCLUSION: Standardized limited oral preoperative fluid intake increases patient comfort and satisfaction with anesthesia care and should be a part of modern day-stay ophthalmologic surgery.

Investigations on the use of fluorescence dyes for labeling dendrimers: cytotoxicity, accumulation kinetics, and intracellular distribution.

Fluorescent dyes (e.g., dansyl, fluoresceine isothiocyanate, or naphthalimide groups) are widely used as markers to study biological properties of drugs. In order to evaluate possible mediated cytotoxicity, we attached three molecules each to 1,3,5-tris(3-propylamino)benzene initially synthesized as core molecule for the design of dendrimers. Cytotoxic effects were only observed for the NO(2)-substituted naphthalimide conjugate. The intracellular distribution was visualized via confocal fluorescence microscopy and pointed to an accumulation in the endosome or nucleus, dependent on the cell line used.

Occurrence of a pneumothorax secondary to malpositioned nasogastric tube: a case report.

We report on the case of a 79-year-old man undergoing a Whipple operation with postoperative unstable respiratory status. Non-invasive ventilation therapy was started and a nasogastric tube (NGT) was placed to lower the risk of gastric accumulation of air. The NGT was placed following recommended clinical procedures. For further examination of the respiratory status, an X-ray was done, which presented the NGT entering the bronchial tree, following the main bronchus down and a newly occurring pneumothorax in the right lung. The NGT was removed immediately and the pneumothorax was treated by drainage of the pleura. Bronchoscopy showed no evidence of tracheobronchial injury. Antibiotic therapy was started and the patient made a full recovery. This case report should remind medical staff of the potential risk of placing a NGT, and gives advice for proper placement to improve patient safety.

Current trends in multiple myeloma management.

Treatment of multiple myeloma, a B-cell cancer, is usually palliative, however, as a result of intensive clinical research there are numerous new treatment options available today. The present review summarizes non-transplant treatment options for multiple myeloma on the basis of available publications. Treatment with new substances, such as immunomodulatory agents, farnesyl transferase inhibitors and apoptosis stimulators, and their mechanisms of action are discussed. In addition to this systematic review of the available evidence on multiple myeloma therapy we have also summarized current recommendations from national and international organizations on aspects of the treatment of multiple myeloma. This should enable readers to see different points of view at a glance and, hopefully, will provide a basis for translation of the available evidence into the best possible therapy.

Cost-effectiveness of oral clodronate compared with oral ibandronate, intravenous zoledronate or intravenous pamidronate in breast cancer patients.

This study aimed to identify the effects of different bisphosphonates in reducing skeletal-related events, and to determine whether there are any differences in their cost-effectiveness, taking into account their efficacy, safety profile and administration routes. A systematic literature search of databases, such as PubMed and the Cochrane Controlled Trials Register, supplemented by the latest congress abstracts from meetings of the European Hematology Association and the American Society of Clinical Oncology was conducted up to November 2006. Important references in reviews published by peer-reviewed journals were also taken into consideration. Our base-case cost-effectiveness analysis for Germany and the UK showed cost savings for oral clodronate therapy compared with other bisphosphonate therapies. In Germany, costs per patient of treatment with oral clodronate were euro1092.38, euro2360.40 and euro2500.29 less than with oral ibandronate, intravenous pamidronate and intravenous zoledronate, respectively. The UK results were similar, the costs per patient of treatment with oral clodronate being euro841.79, euro2989.99 and euro3669.19 less than with oral ibandronate, intravenous pamidronate and intravenous zoledronate, respectively.

Responsiveness to inhaled NO in isolated-perfused lungs from endotoxin-challenged rats is dependent on endogenous nitrite/nitrate synthesis.

BACKGROUND AND OBJECTIVES: In isolated-perfused lungs of lipopolysaccharide (LPS)-challenged rats, vasodilatation to inhaled nitric oxide (NO) is impaired. Inhibition of nitric oxide synthase 2 (NOS2) by aminoguanidine (AG) prevented hyporesponsiveness to inhaled NO. Here, we investigated whether NOS2-mediated nitrite/nitrate synthesis modulates responsiveness to inhaled NO. METHODS: Sprague-Dawley rats received intraperitoneally 0.5 mg kg(-1) LPS. Four hours later, LPS-treated rats received 3, 10 or 30 mg kg(-1) AG or 0.01, 0.1 or 1 mg kg(-1) S-methylisothiourea (SMT) by intraperitoneal injection. Sixteen to eighteen hours later, lungs were isolated and perfused, and pulmonary artery pressure (PAP) was elevated by 6-8 mmHg using the thromboxane analogue U46619. The decrease of PAP in response to inhaled NO and nitrate/nitrite levels in serum and perfusate was measured. RESULTS: In rats treated with LPS alone or 0.01 or 0.1 mg kg(-1) SMT, 40 ppm NO decreased PAP less than in rats treated with AG and 1 mg kg(-1) SMT (-1.8 mmHg (95% confidence interval: -1.5 to -2.1) vs. -6.0 mmHg (-5.7 to -6.3), P < 0.01). Improved NO responsiveness was associated with lower serum and perfusate nitrite/nitrate levels than in rats with hyporesponsiveness to inhaled NO (102 micromol (82-122) vs. 282 micromol (261-303) and 8.1 micromol (6.9-9.3) vs. 19.8 micromol (17.2-22.4), respectively, P < 0.01). CONCLUSIONS: These observations demonstrate that in isolated-perfused lungs of LPS-treated rats, NOS2 inhibition improved responsiveness to inhaled NO. Here, responsiveness to inhaled NO is dependent on the ability of NOS2 inhibitors to reduce nitrite and nitrate levels in serum and released in the lung.

Paclitaxel-loaded microparticles and implants for the treatment of brain cancer: preparation and physicochemical characterization.

The aim of this study was to prepare different types of paclitaxel-loaded, PLGA-based microparticles and lipidic implants, which can directly be injected into the brain tissue. Releasing the drug in a time-controlled manner over several weeks, these systems are intended to optimize the treatment of brain tumors. The latter is particularly difficult because of the blood-brain barrier (BBB), hindering most drugs to reach the target tissue upon systemic administration. Especially paclitaxel (being effective for the treatment of ovarian, breast, lung and other cancers) is not able to cross the BBB to a notable extent since it is a substrate of the efflux transporter P-glycoprotein. Both, biodegradable microparticles as well as small, cylindrical, glycerol tripalmitate-based implants (which can be injected using standard needles) were prepared with different paclitaxel loadings. The effects of several formulation and processing parameters on the resulting drug release kinetics were investigated in phosphate buffer pH 7.4 as well as in a diethylnicotinamide (DENA)/phosphate buffer mixture. Using DSC, SEM, SEC and optical microscopy deeper insight into the underlying drug release mechanisms could be gained. The presence of DENA in the release medium significantly increased the solubility of paclitaxel, accelerated PLGA degradation, increased the mobility of the polymer and drug molecules and fundamentally altered the geometry of the systems, resulting in increased paclitaxel release rates.

[Perioperative evaluation of lung function]. / Perioperative Evaluation der Lungenfunktion.

Respiratory diseases contribute significantly to perioperative morbidity and mortality. Severe pulmonary complications usually emerge postoperatively. To minimise pulmonary risk, the perioperative evaluation of lung function is of major significance, allowing the identification of patient and surgery-related risk factors. In particular, the significance of the intraoperative assessment of lung function has gained in importance over the last few years. The following article describes the possibilities and frontiers of the perioperative assessment of lung function, and focuses especially on the significance of preoperative pulmonary function tests and the intraoperative interpretation of respiratory pressure, flow, and volume loops.

[Characterization of an experimental venous thrombus model with MRI, phlebography and histology]. / Charakterisierung eines experimentellen venösen Thrombosemodells mittels MRT, Phlebographie und Histologie.

INTRODUCTION: Several magnetic resonance (MR) techniques designed to demonstrate the characteristic signal intensity of blood degeneration products of thrombi have been suggested, but the effect of thrombus organization on the MR display, in particular with regard to its temporal evolution, remains to be determined. It is the purpose of this study to develop a stagnation thrombus model in rabbits and to characterize thrombus at different ages with two (MR) imaging techniques, phlebography and histology. MATERIALS AND METHODS: Venous stagnation thrombi were induced in the external jugular veins of rabbits using a minimally invasive radiological technique to produce artificial embolic vascular occlusion and hypercoagulability. Twenty-five animals were divided into 5 groups of 5 animals, and each group underwent 1.5 T MR imaging at 1, 3, 5, 7 and 9 days after thrombus induction using a T1-weighted magnetization-prepared rapid gradient-echo sequence (MP-RAGE: TR 10.4 msec, TE 4.0 msec, FA 15 degrees ) and a T2-weighted fast low-angle shot sequence (FLASH: TR 54 msec, TE 18 msec, FA 15 degrees ). The thrombus length was measured on the T1-weighted images. Thrombus conspicuity, signal intensity, and heterogeneity on T2* weighted images were described using visual scales. Radiographic venography and histology served as reference methods. RESULTS: Thrombi were successfully induced in all animals. The overall thrombus length decreased from 43 +/- 9 (day 1 after induction) to 23 +/- 4 mm (day 9). On 3D-reconstructions of the T1-weighted images, the visible portion of the true thrombus length relative to the overall thrombus length was 0.16 +/- 0.3 (day 1), 0.24 +/- 0.3 (day 3), 0.38 +/- 0.5 (day 5), 0.06 +/- 0.1 (day 7) and 0.00 (day 9). Sixteen of 25 thrombi were detectable with the T2*-weighted technique. The overall thrombus signal intensity decreased with the age of the thrombus from day 1 to day 9. The histological evaluation showed that the rabbit thrombi closely resemble human thrombi morphologically. CONCLUSIONS: The thrombus model closely resembles the human venous stagnation thrombus of different organizational stages. With state-of-the-art MRI techniques, thrombi were only partially displayed with the visibility depending on thrombus age. The model may be suitable for evaluating new and potentially more effective MRI techniques for improved thrombus visualization.

[Methods of airway management in prehospital emergency medicine]. / Methoden des Atemwegsmanagements in der präklinischen Notfallmedizin.

In the majority of emergency situations definite airway control can be achieved by endotracheal intubation with or without preceding bag valve mask ventilation. However, both techniques can fail because of many different reasons. Therefore, alternative techniques for routine anaesthesia and emergency situations are required. In the present article difficulties that may arise using bag valve mask ventilation and endotracheal intubation are discussed and an overview of available alternatives is given.

Postoperative 12-lead ECG predicts peri-operative myocardial ischaemia associated with myocardial cell damage.

Peri-operative myocardial ischaemia is the single most important risk factor for an adverse cardiac outcome after non-cardiac surgery. The present study examines whether intermittent 12-lead ECG recordings can be used as an early warning tool to identify patients suffering from peri-operative myocardial ischaemia and subsequent myocardial cell damage. Fifty-five vascular surgery patients at risk for or with a history of coronary artery disease were monitored for peri-operative myocardial ischaemia using intermittent 12-lead ECG recordings taken pre-operatively and at 15 min, 20 h, 48 h, 72 h and 84 h postoperatively. The effectiveness of the 12-lead ECG was gauged by examining concordance with continuous 3-channel Holter monitoring and capturing peri-operative myocardial ischaemia by serial analyses of creatine kinase myocardial band isoenzyme and cardiac troponin T and I. The incidence of peri-operative myocardial ischaemia detected by 12-lead ECG was 44% and was identifiable in most patients (88%) 15 min after surgery. The incidence of peri-operative myocardial ischaemia detected by continuous monitoring was 53%, with the most severe episodes occurring intra-operatively and during emergence from anaesthesia. The concordance of the 12-lead method with continuous monitoring was 72%. The concordance of creatine kinase myocardial band isoenzyme activity with the 12-lead method was 71% and with Holter monitoring 57%. The concordance of mass concentration of creatine kinase myocardial band with 12-lead ECG recordings was 75%, and the corresponding value for Holter monitoring was 68%. The concordance of cardiac troponin T and I levels with the 12-lead method was 85% and 87%, respectively, and concordance with Holter monitoring was 72% and 66%, respectively. The postoperative 12-lead ECG identified peri-operative myocardial ischaemia associated with subsequent myocardial cell damage in most patients undergoing vascular surgery.

[Preoperative fasting. An update]. / Präoperative Nahrungskarenz. Ein update.

In Germany the predominant standard of preoperative care for elective surgery is fasting after midnight, with the aim of reducing the risk of pulmonary aspiration. However, for the past several years the scientific evidence supporting such a practice has been challenged. Experimental and clinical studies prove a reliable gastric emptying within 2 h suggesting that, particularly for limited intake of clear fluids up to 2 h preoperatively, there would be no increased risk for the patient. In addition, the general incidence of pulmonary aspiration during general anaesthesia (before induction, during surgery and during recovery) is extremely low, has a good prognosis and is more a consequence of insufficient airway protection and/or inadequate anaesthetic depth rather than due to the patient's fasting state. Therefore, primarily to decrease perioperative discomfort for patients, several national anaesthesia societies have changed their guidelines for preoperative fasting. They recommend a more liberal policy regarding per os intake of both liquid and solid food, with consideration of certain conditions and contraindications. The following article reviews the literature and gives an overview of the scientific background on which the national guidelines are based. The intention of this review is to propose recommendations for preoperative fasting regarding clear fluids for Germany as well.

[A thirty-year old bodybuilder with septic shock and ARDS from abuse of anabolic steroids]. / 30-jähriger Bodybuilder mit septischem Schock und ARDS bei Abusus anabolandrogener Steroide.

We report the case of a 30-year-old body builder who developed a gluteal abscess at the site of injection of regularly self-administered anabolic steroids. After breaking the abscess under general anaesthesia, the patient developed septic shock and fulminant adult respiratory distress syndrome (ARDS). In addition to discussing the pathogenesis, differential diagnosis, and treatment, we focus on the immunomodulatory mechanisms of anabolic substances that may have contributed to the course of the disease in this particular patient.

Iron-oxide-enhanced magnetic resonance imaging of atherosclerotic plaques: postmortem analysis of accuracy, inter-observer agreement, and pitfalls.

INTRODUCTION: Contrast-enhanced magnetic resonance (MR) imaging using ultra small superparamagnetic iron oxide (USPIO) particles is a new noninvasive modality for imaging inflammatory atherosclerotic plaques. We determined the accuracy, interobserver agreement, and potential sources of error of this technique by means of postmortem MR imaging of aortic preparations. MATERIAL AND METHODS: Anesthetized atherosclerotic Watanabe heritable hyperlipidemic (WHHL) rabbits were studied after administration of different dosages of intravenous USPIO (DDM 43/34, IDF Berlin, Germany) and different postcontrast time intervals. A (n = 5) received 0 micromol Fe/kg. B (n = 5) received 50 micromol Fe/kg, 8-hour postcontrast interval. C (n = 5) received 50 micromol, 24 hours. D received 200 micromol, 48 hours. The aortas were removed and 3-mm segments prepared for postmortem examination by MR imaging using a T2-weighted gradient-echo sequence (TR/TE/FA; 41 milliseconds/11 milliseconds/15 degrees ), radiography (mammography), and histology (iron staining). USPIO accumulation was defined as the presence of 20 iron-positive cells per microscopic view (x100 magnification). Two independent readers analyzed the MR images and rated their confidence level for a positive MRI finding, defined as a focal signal loss, on a 5-point scale. The results were evaluated by receiver-operator characteristic (ROC) analysis. RESULTS: Of a total of 621 vessel segments technically acceptable for evaluation, 534 were histologically negative and 87 positive. Accuracy, expressed as the area under the ROC curve, was 0.85 for reader 1 and 0.88 for reader 2. Interobserver agreement was 0.67. False-positive findings were established by at least one reader for 121 of the 621 segments, false-negative findings for only 15 segments. Calcifications and mural thrombi were identified as potential sources of error of the method. CONCLUSION: Postmortem USPIO-enhanced MR imaging of atherosclerotic plaques showed a high accuracy and good interobserver agreement in the animal model used here. Further optimization of the method should aim at reducing the rather high percentage of false-positive results.

USPIO-enhanced direct MR imaging of thrombus: preclinical evaluation in rabbits.

PURPOSE: To test the hypothesis that ultrasmall superparamagnetic iron oxide (USPIO) particles may diffuse into nonendothelialized fresh thrombi and thus allow for direct magnetic resonance (MR) imaging of a thrombus. MATERIALS AND METHODS: Stagnation thrombi of different thrombus ages (1, 3, 5, 7, and 9 days) were induced in the external jugular veins of 25 rabbits. Direct MR imaging of thrombi was performed by using a fat-saturated T1-weighted gradient-echo sequence (three-dimensional [3D] magnetization prepared rapid acquisition gradient echo) before and 24 hours after intravenous administration of USPIO (particle size, 25 nm; 200 micromol per kilogram of body weight). Thrombus length on 3D reconstruction images was compared with that depicted on a radiographic venogram and with histologic findings (joint reference standard). In addition, T2*-weighted gradient-echo images were acquired and scored semiquantitatively. RESULTS: The hyperintensity of the thrombus segment depicted on T1-weighted images (thrombus length determined with 3D reconstruction images divided by true thrombus length) increased significantly after administration of contrast medium at a thrombus age of 3 days (0.6 +/- 0.4 [SD] to 0.8 +/- 0.4; P =.02), 5 days (0.1 +/- 0.1 to 1.0 +/- 0.1; P <.001), and 7 days (0 to 0.6 +/- 0.4; P =.02), but not at an age of 1 and 9 days. No significant change in the thrombus signal intensity was observed on T2*-weighted images. CONCLUSION: The animal model showed that direct MR imaging of the thrombus improved 24 hours after USPIO administration with a T1-weighted sequence. No improvement was seen with the T2*-weighted sequence.

Investigations of new lead structures for the design of selective estrogen receptor modulators.

Heterocyclic derivatives of (R,S)/(S,R)-1-(2-chloro-4-hydroxyphenyl)-2-(2,6-dichloro-4-hydroxyphenyl)ethylenediamine (L1) were synthesized and tested for estrogen receptor binding. The selection of the heterocycles was based on theoretical consideration. (2R,3S)/(2S,3R)-2-(2-Chloro-4-hydroxyphenyl)-3-(2,6-dichloro-4-hydroxyphenyl)piperazine 2, (4R,5S)/(4S,5R)-4-(2-chloro-4-hydroxyphenyl)-5-(2,6-dichloro-4-hydroxyphenyl)-2-imidazoline 3, and 4-(2-chloro-4-hydroxyphenyl)-5-(2,6-dichloro-4-hydroxyphenyl)imidazole 4 possess a spatial structure with neighboring aromatic rings as is realized in hormonally active [1,2-diphenylethylenediamine]platinum(II) complexes. The 1,2-diphenylethane pharmacophor, however, cannot adapt an antiperiplanar conformation to interact with the estrogen receptor (ER) comparable to synthetic (e.g., diethylstilbestrol (DES)) or steroidal (e.g., estradiol (E2)) estrogens. Due to the different spatial structures, the heterocycles cause only a marginal displacement of E2 from its binding site (relative binding affinity (RBA) < 0.1%). Nevertheless, unequivocally ER mediated gene activation was verified on the MCF-7-2a cell line. Imidazoline 3 as the most active compound reached the maximum effect of E2 (100% activation) in a concentration of 5 x 10(-7) M, while piperazine 2 and imidazole 4 activate luciferase expression only in a small but significant amount of 20% and 27%, respectively. We therefore assigned these heterocyclic compounds to a second class of hormones (type-II-estrogens), which are attached at the ER at different amino acids than DES or E2 (type-I-estrogens).