Neuroblastomas vary widely in their sensitivities to herpes simplex virotherapy unrelated to virus receptors and susceptibility.

Although most high-risk neuroblastomas are responsive to chemotherapy, relapse is common and long-term survival is < 40%, underscoring the need for more effective treatments. We evaluated the responsiveness of 12 neuroblastoma cell lines to the Δγ134.5 attenuated oncolytic herpes simplex virus (oHSV), Seprehvir (HSV1716), which is currently used in pediatric phase I trials. We found that entry of Seprehvir in neuroblastoma cells is independent of the expression of nectin-1 and the sum of all four known major HSV entry receptors. We observed varying levels of sensitivity and permissivity to Seprehvir, suggesting that the cellular anti-viral response, not virus entry, is the key determinant of efficacy with this virus. In vivo, we found significant anti-tumor efficacy following Seprehvir treatment, which ranged from 6/10 complete responses in the CHP-134 model to a mild prolonged median survival in the SK-N-AS model. Taken together, these data suggest that anti-tumor efficacy cannot be solely predicted based on in vitro response. Whether or not this discordance holds true for other viruses or tumor types is unknown. Our results also suggest that profiling the expression of known viral entry receptors on neuroblastoma cells may not be entirely predictive of their susceptibility to Seprehvir therapy.

Factors associated with thrombosis in pediatric patients with systemic lupus erythematosus.

OBJECTIVE: The risk of thrombosis is increased in patients with systemic lupus erythematosus (SLE). Few studies have assessed factors associated with thrombosis within the pediatric SLE (pSLE) population. We sought to better characterize these associated factors in pSLE patients using the Childhood Arthritis & Rheumatology Research Alliance (CARRA) registry. METHODS: Within the CARRA registry, patients with a history of thrombosis were compared to those without. Univariate logistic regression was used to calculate odds ratios. A multivariable logistic regression model was conducted that included variables from the univariate analysis that had a p value < 0.10 and other variables identified as clinically significant from published literature. RESULTS: Among the 979 pSLE patients in the CARRA registry, 24 (2.5%) patients had a history of arterial thrombosis and 35 (3.6%) of venous thrombosis. In the univariate analysis, the odds ratio of having a thrombotic event were found to be significantly higher in patients with a history of vasculitis, avascular necrosis (AVN), or antiphospholipid antibody (aPL). Similar results were found for vasculitis, AVN, and aPL in the multivariable analysis. CONCLUSION: Our study of pSLE patients suggests that vasculitis, positive APL, and AVN are associated with thrombotic events in this population.

Defective iron-oxide nanoparticles synthesised by high temperature plasma processing: a magnetic characterisation versus temperature.

Magnetic properties and phase compositions of iron-oxide nanoparticles synthesised by a high temperature arc plasma route have been investigated by Mössbauer spectroscopy and high harmonic magnetic AC susceptibility measurements, and correlated with morphological and structural properties for different synthesis conditions. The Mössbauer spectra precisely determined the presence of different iron-oxide fractions in the investigated nanoparticles, while the high harmonic magnetic susceptibility measurements revealed the occurrence of metastable magnetic phases evolving in temperature and time. This study illustrates magnetic properties and dynamics of the magnetic configurations of iron-oxide nanoparticles grown by high temperature plasma, a process less explored so far but extremely useful for synthesising large numbers of nanoparticles for industrial applications.

Incidence of cutaneous malignant melanoma in the Czech Republic: the risks of sun exposure for adolescents.

The Czech Republic reported one of the highest incidence rate in cutaneous melanoma (CM) in Europe and because this incidence has been increasing, mainly among young people, the main goal of our study was to establish sun exposure behavior risk factors for CM formation and to evaluate whether the young generation of Czechs is exposed to a higher risk of CM than the older generation. A questionnaire-based case-control study was conducted. We obtained 978 completed questionnaires: 216 from patients with CM and 762 from healthy respondents. The healthy individuals were further divided to adolescents (n = 460) and older respondents (n = 302). Three logistic regression models were developed: 1. patients with CM vs. healthy older respondents, 2. adolescents vs. healthy older respondents, and 3. patients with CM vs. adolescents. The main risk factors for all three models were the number of sunburn episodes and the use of the sunscreen in the childhood. The most alarming results for adolescents included: all day sun exposure, including times of maximum risk (11 AM to 3 PM), inadequate use of sunscreen in adulthood, and frequent mountain holidays. Our results show that sun-safety in the young generation is satisfactory, when the responsibility for sun exposure behavior is in the hands of their parents; however, when children become adolescents, they become immune to sun-safety and risk prevention campaigns and their behavior becomes much more risky. Our results further suggest the sun-safety campaigns need to be modified in such a way as to have greater impact and influence on adolescent sun-risk behaviors.

Plasma protein binding may reduce antimicrobial activity by preventing intra-bacterial uptake of antibiotics, for example clindamycin.

OBJECTIVES: although plasma protein binding (PPB) is accepted to be an essential factor in reducing antimicrobial activity, little is known about the underlying mechanisms. One possibility includes impaired penetration of an antimicrobial into bacterial cells in the presence of PPB. As a prerequisite for testing this hypothesis an optimized medium displaying high protein binding without impairing bacterial growth had to be identified for our model compound clindamycin. METHODS: determination of PPB, bacterial growth and antimicrobial killing was performed in Mueller-Hinton broth (MHB) containing various amounts of human albumin or serum. [(3)H]clindamycin was used to investigate clindamycin penetration into Staphylococcus aureus. RESULTS: of all investigated media only MHB(50%serum) and MHB(70%serum) achieved protein binding comparable to pure serum. In contrast, MHB(20%serum) and most media containing only albumin demonstrated considerably lower protein binding. Pure serum resulted in bacterial growth inhibition compared with MHB while MHB(16%albumin) and MHB(50%serum) did not result in significant differences in bacterial count after 24 h. However, in both MHB(16%albumin) and MHB(50%serum) the antimicrobial activity of clindamycin was reduced by >2 log(10) cfu/mL compared with pure MHB. The radioactive signal after administration of [(3)H]clindamycin to S. aureus was significantly decreased in pure serum as well as in MHB(16%albumin) and MHB(50%serum), while no significant difference was observed for MHB(4%albumin) and MHB(20%serum). CONCLUSIONS: reduction of the intracellular radioactive signal in the presence of serum proteins correlated both with the degree of protein binding and reduction of antimicrobial activity supporting the hypothesis of impairment of activity by PPB by reducing intra-bacterial antimicrobial concentrations.

A task failure has no effect on the electromechanical delay of the peroneus longus.

OBJECTIVE: Ankle inversion injuries represent the most common trauma sustained by athletes. Muscle fatigue from activity may contribute to a delay in the response of the ankle proprioceptors and dynamic restraints during unexpected inversion. The purpose of this investigation was to determine if the electromechanical delay (EMD) of the peroneus longus is influenced by a task failure exercise. SUBJECTS: Sixteen subjects (age 20 +/- 1.1 y; mass 71.6 +/- 12.5 kg; height 173.0 +/- 8.7 cm; 9 male, 1 female) with no lower extremity injuries reported for data collection. MEASUREMENTS: Data were collected from each subject's dominant leg using surface electromyography (EMG). Electrodes were applied over the peroneus longus (PL) using a standard protocol. A stimulating electrode was applied to the common peroneal nerve. Subjects were placed in a monopedal stance on a force platform. A low amplitude, short duration stimulus was applied to the common peroneal nerve. The EMG was used to determine timing of the M wave and the force platform was used to determine the onset of foot pronation. Once 6 trials were recorded, subjects completed 2 sets of an isotonic activity that isolated the peroneals. The task was completed to failure for each set. Immediately following the task failure exercise, subjects returned to the force platform for 6 additional trials recorded as before. Analysis of data was performed by determining the onset of the M wave as the beginning of positive EMG activity following the end of the imposed stimulus response. This point was superimposed on the force platform curve and the point at which a 10 N.m force change occurred was used to calculate the EMD (time difference between the force platform indicator and the M wave indicator). RESULTS: Average EMD prior to the task failure exercise was 13.35 +/- 3.47 ms. Following the task failure exercise, the average EMD was 12.67 +/- 3.86 ms. A paired samples t test revealed no significant differences with regard to EMD between pre- and post-task failure exercise for the PL (p = 0.448). CONCLUSION: We concluded that the task failure exercise did not affect the electromechanical delay of the PL.

Transferring the entatic-state principle to copper photochemistry.

The entatic state denotes a distorted coordination geometry of a complex from its typical arrangement that generates an improvement to its function. The entatic-state principle has been observed to apply to copper electron-transfer proteins and it results in a lowering of the reorganization energy of the electron-transfer process. It is thus crucial for a multitude of biochemical processes, but its importance to photoactive complexes is unexplored. Here we study a copper complex-with a specifically designed constraining ligand geometry-that exhibits metal-to-ligand charge-transfer state lifetimes that are very short. The guanidine-quinoline ligand used here acts on the bis(chelated) copper(I) centre, allowing only small structural changes after photoexcitation that result in very fast structural dynamics. The data were collected using a multimethod approach that featured time-resolved ultraviolet-visible, infrared and X-ray absorption and optical emission spectroscopy. Through supporting density functional calculations, we deliver a detailed picture of the structural dynamics in the picosecond-to-nanosecond time range.

The effects of external support on electromechanical delay of the peroneus longus muscle.

Ankle taping and bracing is commonly used in athletics and both have been shown to be effective in reducing injury. Ankle proprioception has been shown to increase with external support due to the activation of cutaneous mechanoreceptors, however, the sensorimotor effect has not been studied Electromechanical delay (EMD) is defined as the time lag from the onset of electrical activity in the muscle to the subsequent mechanical response. The purpose of this investigation was to measure and compare the EMD of the peroneus longus muscle during ankle unsupported, braced, and taped conditions. Thirty-one (10 male, 21female) healthy, college-aged subjects participated in the study (age: 20.9 +/- 1.8 years, mass 70.3 +/- 15.8 kg, height 171.1 +/- 9.6 cm). Each subject was assigned a random order for the three external support conditions. The subject was positioned on a force platform and instructed to actively evert the ankle. We examined the time lag between the onset of electrical activity in the peroneus longus muscle and a change in force as detected by the force platform. Five trials were completed for each condition and a repeated measures ANOVA was used to determine statistical significance. The results showed no significant difference between the three external support conditions. We concluded that external support through taping and bracing does not affect the EMD of the peroneus longus muscle in healthy subjects.

CGP 48664, a new S-adenosylmethionine decarboxylase inhibitor with broad spectrum antiproliferative and antitumor activity.

Inhibitors of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (SAMDC), derived from methylglyoxal-bis(guanylhydrazone) (MGBG), have been shown to have significant antitumor activity in several human solid tumor systems (U. Regenass et al., Cancer Res., 52:4712-4718, 1992). From an ongoing effort to synthesize derivatives with increased enzyme specificity and potency and improved antitumor efficacy, we have now identified CGP 48664, a 4-amidinoindan-1-one 2'-amidinohydrazone (J. Stanek et al., J. Med. Chem., 36:2168-2171, 1993). The compound displays potent inhibition of SAMDC (50% inhibitory concentration, 5 nM), modest inhibition of diamine oxidase (50% inhibitory concentration, 4 microM), and no detectable inhibition of ornithine decarboxylase. CGP 48664 inhibits the growth of a panel of human and mouse tumor cell lines, including one which expresses the multidrug resistance phenotype, with 50% inhibitory concentrations ranging between 0.3 and 3 microM. CGP 48664 does not seem to utilize the polyamine transport carrier system since it competes poorly with spermidine for uptake into L1210 cells (Ki 161 microM) and inhibits the growth of polyamine transport-deficient Chinese hamster ovary cells. Relative to MGBG or previously described MGBG analogues, CGP 48664 accumulates to much lower intracellular concentrations. Treatment of the L1210 cell for 48 h with 3 microM CGP 48664 decreases SAMDC activity to < 10% of control and initiates a compensatory 3-fold rise in ornithine decarboxylase. Consistent with SAMDC inhibition, putrescine pools increase 10-fold, whereas spermidine and spermine pools fall to < 10% of control. In contrast to MGBG, CGP 48664 displays attenuated antimitochondrial activity as indicated by a lack of effect on pyruvate oxidation and mitochondrial DNA levels under treatment conditions which inhibit cell proliferation. Specificity of drug action was indicated further by prevention of L1210 cell growth inhibition by exogenous spermidine or spermine. More convincingly, Chinese hamster ovary cells made approximately 1000-fold resistant by chronic exposure to the analogue were found to selectively overexpress SAMDC mRNA due to gene amplification. The new SAMDC inhibitor showed potent antitumor activity against syngeneic tumors (B16 melanoma and Lewis lung carcinoma) and nude mouse human tumor xenografts (T-24 bladder carcinoma, SK MEL-24 melanoma, and MALME-3M melanoma). On the basis of its novel structure, its apparent specificity of action, and its potent antitumor activity, CGP 48664 is the candidate drug for further preclinical development.

Morphological evidence for an apparent lysosomotropic activity by unsaturated putrescine analogues.

Treatment of cultured L1210 cells with the putrescine analogue, 2,5-diamino-3-hexyne, at 0.5 nM resulted in the rapid (1-2 h) appearance of numerous cytoplasmic vacuoles which were highly visible by light microscopy. Ultrastructural examination revealed that the vacuoles contained numerous membrane vesicles and electron-dense structures resembling endosomal elements. Other cellular organelles were unaffected by the drug. The overall morphological effect by 2,5-diamino-3-hexyne was nearly identical to that produced in the same cells by the known lysosomotropic agent, chloroquine. Since the putrescine analogue, 1,4-diamino-2-butyne at 1.2 mM, also produced comparable cytoplasmic vacuolation, and putrescine itself failed to do so at concentrations as high as 5 mM, it was concluded that the apparent lysosomotropic activity of the putrescine analogues was probably due to their weaker basicity related to the presence of an internal triple bond. Although it is uncertain whether the effect of the analogues on the endosomal system is related to the natural function of polyamines, the finding points out the previously unrecognized potential for certain polyamine analogues to act in this manner.

New S-adenosylmethionine decarboxylase inhibitors with potent antitumor activity.

Methylglyoxal bis(guanylhydrazone) (MGBG) has been studied clinically as an antitumor and antileukemic agent and is recognized as a potent but nonspecific inhibitor of the key polyamine biosynthetic enzyme, S-adenosylmethionine decarboxylase (SAMDC). A series of four SAMDC inhibitors with structural features similar to MGBG have been found to have improved potency and specificity toward the target enzyme, SAMDC. Relative to MGBG, the new derivatives were much more effective in inhibiting partially purified preparations of SAMDC (50% inhibitory concentration, 10 to 100 nM), much less effective at inhibiting diamine oxidase, and inactive toward ornithine decarboxylase. The inhibitors varied relative to MGBG in their ability to compete with spermidine for uptake, with two being similar and two being less effective. Against L1210 leukemic cells and T24 bladder carcinoma cells, the compounds were slightly less effective than MGBG at inhibiting cell growth, with 50% inhibitory concentration values of 1 to 10 microM as compared with 0.5 and 1.1 microM, respectively, for MGBG. Under 50% growth-inhibitory conditions, the inhibitors decreased SAMDC activity, increased ornithine decarboxylase activity and putrescine pools, and markedly depleted spermidine and spermine pools of L1210 cells. At the same time, mitochondrial integrity as assessed by whole-cell pyruvate oxidation and mitochondrial DNA content was not affected as it was with MGBG. At doses less than one tenth that of the maximally tolerated dose, all of the new inhibitors strongly suppressed the growth of B16 melanoma in vivo with minimal weight loss or toxicity. At doses less than one sixth the maximally tolerated dose, they effectively inhibited the growth of T24 human bladder carcinoma xenografts. In these same systems, MGBG showed only marginal antitumor activity. These studies identify two potent and efficacious inhibitors of SAMDC as potential antitumor agents and reaffirm the importance of SAMDC as a target in anticancer drug discovery.

A new approach to configurable primary data collection.

BACKGROUND AND OBJECTIVES: The formats, semantics and operational rules of data processing tasks in genomics (and health in general) are highly divergent and can rapidly change. In such an environment, the problem of consistent transformation and loading of heterogeneous input data to various target repositories becomes a critical success factor. The objective of the project was to design a new conceptual approach to configurable data transformation, de-identification, and submission of health and genomic data sets. Main motivation was to facilitate automated or human-driven data uploading, as well as consolidation of heterogeneous sources in large genomic or health projects. METHODS: Modern methods of on-demand specialization of generic software components were applied. For specification of input-output data and required data collection activities, we propose a simple data model of flat tables as well as a domain-oriented graphical interface and portable representation of transformations in XML. Using such methods, the prototype of the Configurable Data Collection System (CDCS) was implemented in Java programming language with Swing graphical interfaces. The core logic of transformations was implemented as a library of reusable plugins. RESULTS: The solution is implemented as a software prototype for a configurable service-oriented system for semi-automatic data collection, transformation, sanitization and safe uploading to heterogeneous data repositories-CDCS. To address the dynamic nature of data schemas and data collection processes, the CDCS prototype facilitates interactive, user-driven configuration of the data collection process and extends basic functionality with a wide range of third-party plugins. Notably, our solution also allows for the reduction of manual data entry for data originally missing in the output data sets. CONCLUSIONS: First experiments and feedback from domain experts confirm the prototype is flexible, configurable and extensible; runs well on data owner's systems; and is not dependent on vendor's standards.

Decreased morbidity and mortality of autologous hematopoietic transplants for children with malignant central nervous system tumors: the 'Head Start' trials, 1991-2009.

Since 1991, three sequential prospective clinical trials have been conducted by the 'Head Start' (HS) Consortium in which young children with newly-diagnosed malignant central nervous system (CNS) tumors were treated with induction chemotherapy followed by single-cycle marrow-ablative chemotherapy and autologous hematopoietic rescue as a means of improving disease cure rate and quality of survival through avoidance (<6 years old at diagnosis) or reduction (6-10 years old) of brain irradiation. Bone Marrow (HS I) or filgrastim-mobilized peripheral hematopoietic cells (HS II and III) were obtained following recovery from the first and/or second induction cycles. Radiotherapy was administered following all chemotherapy only for patients with residual tumor following completion of induction or with age greater than 6 years at diagnosis. Two hundred and twenty-six children were enrolled on three consecutive HS trials with primary malignant CNS tumors and underwent marrow-ablative chemotherapy. The 100-day treatment-related mortality (TRM) steadily declined as did grade IV transplant-related oropharyngeal mucositis. Factors most likely associated with the decrease in TRM and morbidity are increasing experience with the marrow-ablative chemotherapy regimen combined with improved leukapheresis and post-reinfusion supportive care techniques, contributing toward improved overall survival.

Pilot PET Study to Assess the Functional Interplay Between ABCB1 and ABCG2 at the Human Blood-Brain Barrier.

ABCB1 and ABCG2 work together at the blood-brain barrier (BBB) to limit brain distribution of dual ABCB1/ABCG2 substrates. In this pilot study we used positron emission tomography (PET) to assess brain distribution of two model ABCB1/ABCG2 substrates ([(11) C]elacridar and [(11) C]tariquidar) in healthy subjects without (c.421CC) or with (c.421CA) the ABCG2 single-nucleotide polymorphism (SNP) c.421C>A. Subjects underwent PET scans under conditions when ABCB1 and ABCG2 were functional and during ABCB1 inhibition with high-dose tariquidar. In contrast to the ABCB1-selective substrate (R)-[(11) C]verapamil, [(11) C]elacridar and [(11) C]tariquidar showed only moderate increases in brain distribution during ABCB1 inhibition. This provides evidence for a functional interplay between ABCB1 and ABCG2 at the human BBB and suggests that both ABCB1 and ABCG2 need to be inhibited to achieve substantial increases in brain distribution of dual ABCB1/ABCG2 substrates. During ABCB1 inhibition c.421CA subjects had significantly higher increases in [(11) C]tariquidar brain distribution than c.421CC subjects, pointing to impaired cerebral ABCG2 function.

Mixed valence state in ironporphyrin aggregates.

In biological systems, metalloporphyrins play a central role in energy and electron transfer process. Our aim is to understand the influence of ligands and iron coordination of ironporphyrin on the electron transfer. The lyophilized ironporphyrin, enriched in 57Fe up to 90% has been studied by Mössbauer spectroscopy between 2.8 and 313 K. Above room temperature the bounded diffusion of the ferric iron was observed. Below 293 K a part of iron appears in mixed Fe+3<==>Fe+2 valence state with 10 meV activation energy for the electron trapping. Below 4 K a part of iron shows magnetic ordering with a broad distribution of the hyperfine field. The results are discussed in terms of metalloporphyrin aggregation process.

The Novartis compound archive -- from concept to reality.

As HTS technologies come of age, pharmaceutical companies are focusing increasingly on the quality of their screening collections. Storage conditions and their influence on compound stability and solubility are debated intensely. At Novartis, a strategy was developed that is different to most other companies: (1) compounds unsuitable for storage in solution are excluded by computational methods; (2) compounds are stored at 4 degrees C/20% relative humidity in a DMSO/water mixture to avoid freeze-thaw cycles and water uptake and to allow rapid plate replication; (3) resolubilisation of compounds at regular intervals.

Identification of a decidua-specific enhancer on the human prolactin gene with two critical activator protein 1 (AP-1) binding sites.

Deletion analysis of the human PRL promoter in endometrial stromal cells decidualized in vitro revealed a 536-bp enhancer located between nucleotide (nt) -2,040 to -1,505 in the 5'-flanking region. The 536-bp enhancer fragment ligated into a thymidine kinase (TK) promoter-luciferase reporter plasmid conferred enhancer activity in decidual-type cells but not nondecidual cells. DNase I footprint analysis of decidualized endometrial stromal cells revealed three protected regions, FP1-FP3. Transfection of overlapping 100-bp fragments of the 536-bp enhancer indicated that FP1 and FP3 each conferred enhancer activity. Gel shift assays indicated that both FP1 and FP3 bind activator protein 1 (AP-1), and JunD and Fra-2 are components of the AP-1 complex in decidual fibroblasts. Mutation of the AP-1 binding site in either FP1 or FP3 decreased enhancer activity by approximately 50%, while mutation of both sites almost completely abolished activity. Coexpression of the 536-bp enhancer and A-fos, a dominant negative to AP-1, decreased enhancer activity by approximately 70%. Conversely, coexpression of Fra-2 in combination with JunD or c-Jun and p300 increased enhancer activity 6- to 10-fold. Introduction of JunD and Fra-2 into nondecidual cells is sufficient to confer enhancer activity. JunD and Fra-2 protein expression was markedly increased in secretory phase endometrium and decidua of early pregnancy (high PRL content) compared with proliferative phase endometrium (no PRL). These investigations indicate that the 5'-flanking region of the human PRL gene contains a decidua-specific enhancer between nt -2,040/-1,505 and AP-1 binding sites within this enhancer region are critical for activity.

Ovarian 'tumor' of the adrenogenital syndrome: the first reported case.

We report the case of a 36-year-old woman with congenital adrenal hyperplasia from 21-hydroxylase deficiency who had been receiving replacement therapy with corticosteroids since birth. At the age of 35 years, she developed abrupt aggravation of her virilizing symptoms and underwent an adrenalectomy and partial left oophorectomy. Persistent virilization and high testosterone levels led to right oophorectomy and completion left oophorectomy 6 months later. Each adnexa contained ovarian or paraovarian soft brown masses that on microscopic examination were identical to the testicular tumor of the adrenogenital syndrome. This represents the first reported case of this pathology (well known in the testis) in the ovary.

2-substituted 3-(aminooxy)propanamines as inhibitors of ornithine decarboxylase: synthesis and biological activity.

1-Amino-3-(aminooxy)-2-propanol (6a) has been synthesized and found to inhibit rat liver ornithine decarboxylase (ODC) with an IC50 in the nanomolar range. Compound 6a served as a basis for the design of new enzyme inhibitors, which led to the identification of 3-(aminooxy)-2-fluoropropanamine (15) as a new powerful enzyme blocker. Compound 15 inhibited ODC at 3 times lower concentrations than 6a and 3-(aminooxy)propanamine (APA), and it was superior to APA as an antiproliferative agent in inhibiting the growth of human T24 bladder carcinoma cells in vitro.

Synthesis and aromatase inhibitory activity of novel 1-(4-aminophenyl)-3-azabicyclo[3.1.0]hexane- and -[3.1.1]heptane-2,4- diones.

The synthesis of 3-(cyclohexymethyl)-1-(4-aminophenyl)-3-azabicyclo[3.1.0]hexane-2, 4-dione (1h), with its optical enantiomers, and a series of novel achiral 1-(4-aminophenyl)-3-azabicyclo[3.1.1]haptane-2,4-diones (2a-i,k) is described. These compounds were tested in vitro for inhibition of human placental aromatase, a cytochrome-P450-dependent enzyme responsible for the conversion of androgens to estrogens. All of them displayed enzyme-inhibiting activity, and 3-cyclohexyl derivative 2g and 3-cyclohexylmethyl derivative 1h both proved more potent (greater than 140-fold) than the clinically effective agent aminoglutethimide [3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione, AG]. As with AG and its derivatives, the 1R-(+)-enantiomer of 1h was responsible for the enzyme inhibitory activity. These novel compounds are of interest as potential drugs for endocrine therapy of hormone-dependent tumors, e.g. breast cancer.