Class Of Synthetic Compounds Research Articles

Biological activities of metal complexes with Schiff base

Abstract Schiff bases are a class of synthetic compounds that form when primary amines combine with aldehydes or ketones. These compounds are incredibly important across various fields, such as biology, catalysis, and optics, due to their diverse features. One notable aspect is their ability to form complexes with transition metals, which opens up a wide range of potential uses, particularly in human systems. In the human body, Schiff base metal complexes display a range of biological actions, including antibacterial, antifungal, anticancer, and antimalarial properties. The versatility of Schiff bases in reacting with different transition metals gives these complexes intriguing potential for addressing biological issues and treating diseases. This article explores various examples of Schiff bases, metal complexes, and their associated ligands, highlighting their usefulness in a variety of biological applications. The potential of Schiff base metal complexes as valuable agents in resolving medical difficulties and advancing biomedical research is emphasized.

5613423 TREATMENT OF ERYTHROID PRECURSOR CELLS FROM β-THALASSEMIC PATIENTS WITH ISOXAZOLE DERIVATIVES: POTENT INDUCTION OF FETAL HEMOGLOBIN

Background: Increased production of fetal hemoglobin (HbF) can be beneficial for β-thalassemia patients and several clinical trials in β-thalassemia and/or sickle-cell disease (SCD) are ongoing using HbF inducers, such as NCT01245179 (based on the HDAC inhibitor Panobinostat), NCT00790127 (based on 2,2-dimethylbutyrate, HQK-1001) and NCT03877809 (based on the mTOR inhibitor sirolimus). Methods: In this context, new molecules able to induce HbF are needed. In this communication, we have studied in deep a new class of promising HbF inducers characterized by an isoxazole chemical skeleton. These derivatives are 3,4-isoxazolediamide compounds recently synthesized in our laboratories. The original structures of two natural molecules, geldanamycin and radicicol, known to be natural Hsp (Heat Shot Protein) inhibitors, were modified to lead to a novel class of synthetic compounds, containing the isoxazole nucleus, and displaying potent and selective inhibition of Hsp90. Here we used erythroid precursors cells (ErPCs) isolated from β-thalassemic patients and treated with appropriate concentrations of 8 isoxazole derivatives previously demonstrated to be able to induce erythroid differentiation of K562 cells. Results: We demonstrated the high efficacy of the analyzed isoxazoles in inducing HbF. Some derivatives demonstrated an activity even higher than other HbF inducers used as positive controls, such as Hydroxyurea (HU) or Sirolimus. Most of the isoxazole derivatives displayed high effects in decreasing the excess of free α-globin chains in treated ErPCs. All the compounds were assayed for genotoxicity through the Ames test, employing the histidine-requiring Salmonella typhimurium mutant TA 97A, TA98, TA100 and TA1535 strains that allow to check frameshift mutation and base-pair substitution, with and without metabolic activation induced by S9 Mix. These assays excluded any drawbacks related to genotoxicity. Summary - Conclusion: We may therefore conclude that these novel isoxazoles could be proposed for clinical studies for possible therapeutic application for the treatment of β-thalassemia. These compounds have been recently patented as potential therapeutic agents for β-thalassemia (US Patent 11077116). Acknowledgements This study was sustained by the Wellcome Trust (innovator award 208872/Z/17/Z), by AIFA (AIFA-2016-02364887) and by the UE THALAMOSS Project (Thalassemia Modular Stratification System for Personalized Therapy of Βeta-Thalassemia; no. 306201-FP7-HEALTH-2012-INNOVATION-1). We thank A.L.T. (Associazione per la lotta alla Talassemia) “Rino Vullo” - Ferrara, and A.V.L.T. (Associazione Veneta per la Lotta alla Talassemia) “Elio Zago” - APS – Rovigo.

Applications of medicinal chemistry for drug discovery against Acanthamoeba infections.

Acanthamoeba is a genus of free-living amoebae, pervasively found in the environment. Most of its pathogenic species are the causative agent of sight-threatening Acanthamoeba keratitis and fatal granulomatous amoebic encephalitis. Despite the advancements in the field of chemotherapy, treating Acanthamoeba infections is still challenging due to incomplete knowledge of the complicated pathophysiology. In case of infection, the treatment regimen for the patients is often ineffective due to delayed diagnosis, poor specificity, and side-effects. Besides the resistance of Acanthamoeba cysts to most of the drugs, the recurrence of infection further complicates the recovery. Thus, it is necessary to develop an effective treatment which can eradicate these rare, but serious infections. Based on various computational and in vitro studies, it has been established that the synthetic scaffolds such as heterocyclic compounds may act as potential drug leads for the development of antiamoebic drugs. In this review, we report different classes of synthetic compounds especially heterocyclic compounds which have shown promising results against Acanthamoeba. Moreover, the antiamoebic activities of synthetic compounds with their possible mode of actions against Acanthamoeba, have been summarized and discussed in this review.

A Synthetic Biology Approach Using Engineered Bacteria to Detect Perfluoroalkyl Substance (PFAS) Contamination in Water.

Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic compounds used industrially for a wide variety of applications. These PFAS compounds are very stable and persist in the environment. The PFAS contamination is a growing health issue as these compounds have been reported to impact human health and have been detected in both domestic and global water sources. Contaminated water found on military bases poses a potentially serious health concern for active duty military, their families, and the surrounding communities. Previous detection methods for PFAS in contaminated water samples require expensive and time-consuming testing protocols that limit the ability to detect this important global pollutant. The main objective of this work was to develop a novel detection system that utilizes a biological reporter and engineered bacteria as a way to rapidly and efficiently detect PFAS contamination. The United States Air Force Academy International Genetically Engineered Machine team is genetically engineering Rhodococcus jostii strain RHA1 to contain novel DNA sequences composed of a propane 2-monooxygenase alpha (prmA) promoter and monomeric red fluorescent protein (mRFP). The prmA promoter is activated in the presence of PFAS and transcribes the mRFP reporter. The recombinant R. jostii containing the prmA promoter and mRFP reporter respond to exposure of PFAS by activating gene expression of the mRFP. At 100 µM of perfluorooctanoic acid, the mRFP expression was increased 3-fold (qRT-PCR). Rhodococcus jostii without exposure to PFAS compounds had no mRFP expression. This novel detection system represents a synthetic biology approach to more efficiently detect PFAS in contaminated samples. With further refinement and modifications, a similar system could be readily deployed in the field around the world to detect this critical pollutant.

Pro-apoptotic activity of novel synthetic isoxazole derivatives exhibiting inhibitory activity against tumor cell growth in vitro.

In order to develop potential anticancer agents stimulating apoptosis, novel 3,4-isoxazolediamide and 4,5,6,7-tetrahydro-isoxazolo-[4,5-c]-pyridine derivatives have been synthetized. The original structures of geldanamycin and radicicol, which are known natural heat shock protein (HSP) inhibitors, were deeply modified because both of them exhibit several drawbacks, such as poor solubility, hepatotoxicity, intrinsic chemical instability or deprivation of the in vivo activity. This novel class of synthetic compounds containing the isoxazole nucleus exhibited potent and selective inhibition of HSP90 in previous studies. Biological assays (focusing on in vitro antiproliferative effects and pro-apoptotic activity) in human erythroleukemic K562 cells (as a model system referring to tumor cells grown in suspension), glioblastoma U251-MG and glioblastoma temozolomide (TMZ)-resistant T98G cell lines (two model systems referring to tumor cells grown attached to the flask), were performed. Almost all isoxazole derivatives demonstrated significant antiproliferative and pro-apoptotic activities, showing induction of both early and late apoptosis of K562 cells. Different effects were observed on the glioma U251-MG and T98G cells, depending on the structure of the analogues. Antiproliferative and pro-apoptotic activities in K562 cells were associated with the activation of the erythroid differentiation program. The present study demonstrated that 3,4-isoxazolediamide and 4,5,6,7-tetrahydro-isoxazolo-[4,5-c]-pyridine derivatives should be considered for in vivo studies focusing on the development of anticancer drugs acting, at least partially, via activation of apoptosis.

Structural States of Hdm2 and HdmX: X-ray Elucidation of Adaptations and Binding Interactions for Different Chemical Compound Classes.

Hdm2 (human MDM2, human double minute 2 homologue) counteracts p53 function by direct binding to p53 and by ubiquitin-dependent p53 protein degradation. Activation of p53 by inhibitors of the p53-Hdm2 interaction is being pursued as a therapeutic strategy in p53 wild-type cancers. In addition, HdmX (human MDMX, human MDM4) was also identified as an important therapeutic target to efficiently reactivate p53, and it is likely that dual inhibition of Hdm2 and HdmX is beneficial. Herein we report four new X-ray structures for Hdm2 and five new X-ray structures for HdmX complexes, involving different classes of synthetic compounds (including the worldwide highest resolutions for Hdm2 and HdmX, at 1.13 and 1.20 Å, respectively). We also reveal the key additive 18-crown-ether, which we discovered to enable HdmX crystallization and show its stabilization of various Lys residues. In addition, we report the previously unpublished details of X-ray structure determinations for eight further Hdm2 complexes, including the clinical trial compounds NVP-CGM097 and NVP-HDM201. An analysis of all compound binding modes reveals new and deepened insight into the possible adaptations and structural states of Hdm2 (e.g., flip of F55, flip of Y67, reorientation of H96) and HdmX (e.g., flip of H55, dimer induction), enabling key binding interactions for different compound classes. To facilitate comparisons, we used the same numbering for Hdm2 (as in Q00987) and HdmX (as in O15151, but minus 1). Taken together, these structural insights should prove useful for the design and optimization of further selective and/or dual Hdm2/HdmX inhibitors.

Simultaneous Determination of 11 Illicit Phenethylamines in Hair by LC-MS-MS: In Vivo Application.

Existing phenethylamines are a class of synthetic compounds that differ from each other only in small changes to a largely conserved chemical structure. The recreational and illicit use of phenethylamines is a widespread problem. A simple procedure for the simultaneous quantitative determination in hair of 11 phenethylamines that are officially recognized as illicit by Italian legislation (p-methoxyamphetamine; p-methoxymethamphetamine; 3,4,5-trimethoxyamphetamine; 2,5-dimethoxyamphetamine; 2,5-dimethoxy-4-methylamphetamine; 2,5-dimethoxy-4-ethylamphetamine; 2,5-dimethoxy-4-bromoamphetamine; 2,5-dimethoxy-4-bromophenethylamine; 2,5-dimethoxy-4-iodophenethylamine; 2,5-dimethoxy-4-ethylthiophenethylamine and 2,5-dimethoxy-4-n-propylthiophenethylamine) has been developed and validated. Extraction from the matrix was performed after incubation in methanolic HCl and filtered reconstituted extracts were injected into a liquid chromatography/tandem mass spectrometry system (LC-MS-MS) without any further purification steps. This validated LC-MS-MS method has been used to determine the in vivo accumulation/retention of the above target analytes in hair after repeat oral administration to rats. This experiment further permitted investigation of the effect of pigmentation on the uptake of these phenethylamines by hair and the effect of hair pigmentation. The developed method could potentially be used for forensic and toxicological purposes, in the detection and quantitation of these illicit substances in human hair in workplace drug testing; drug-facilitated crime investigation; driver re-licensing; determining drug abuse history and postmortem toxicology.

Cord blood gene expression supports that prenatal exposure to perfluoroalkyl substances causes depressed immune functionality in early childhood

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are a class of synthetic compounds that have widespread use in consumer and industrial applications. PFAS are considered environmental pollutants that have various toxic properties, including effects on the immune system. Recent human studies indicate that prenatal exposure to PFAS leads to suppressed immune responses in early childhood. In this study, data from the Norwegian BraMat cohort was used to investigate transcriptomics profiles in neonatal cord blood and their association with maternal PFAS exposure, anti-rubella antibody levels at 3 years of age and the number of common cold episodes until 3 years. Genes associated with PFAS exposure showed enrichment for immunological and developmental functions. The analyses identified a toxicogenomics profile of 52 PFAS exposure-associated genes that were in common with genes associated with rubella titers and/or common cold episodes. This gene set contains several immunomodulatory genes (CYTL1, IL27) as well as other immune-associated genes (e.g. EMR4P, SHC4, ADORA2A). In addition, this study identified PPARD as a PFAS toxicogenomics marker. These markers can serve as the basis for further mechanistic or epidemiological studies. This study provides a transcriptomics connection between prenatal PFAS exposure and impaired immune function in early childhood and supports current views on PPAR- and NF-κB-mediated modes of action. The findings add to the available evidence that PFAS exposure is immunotoxic in humans and support regulatory policies to phase out these substances.

Identification of naphthol derivatives as novel antifeedants and insecticides. 1.

A series of β-naphthol-derived 2-aminobenzothiazolomethylnaphthol derivatives (4a-4q) were synthesized and purified in excellent yields (86-94%) using green protocols and screened for their antifeedant and toxic activities against tobacco caterpillar (Spodoptera litura) and castor semilooper (Achaea janata) using no-choice leaf disk and topical bioassay methods. Four of them, 4d, 4f, 4i, and 4j, were identified to be potent antifeedants with ED50 values of 16.4, 19.3, 7.0, and 5.2 μg/cm(2) against S. litura and 13.9, 17.2, 10.2, and 7.7 μg/cm(2) against A. janata, respectively, and the mortality rate is >95% for 4i and 4j in the case of S. litura and 4j in case of A. janata at a dosage of 0.2 μg/insect. Compounds 4d, 4i, and 4m are moderately toxic to A. janata only. Overall, this study identified a novel class of synthetic compounds that do not belong to organochlorides, organophosphates, carbamates, or neonicotinoids as strong antifeedants as well as insecticides.

Identification and characterisation of a novel heat shock protein 90 inhibitor ONO4140

Heat shock protein (Hsp) 90 is a key component of the super-chaperone complex that maintains functionally active conformation of various client proteins. Many of these client proteins regulate important nodal points in multiple signalling pathways that promote cancer cell growth and survival. Inhibitors of Hsp90, therefore, have the potential of functioning as anti-cancer agents with pleiotropic effects. Identification of novel Hsp90 inhibitors with more favourable pharmacological properties is a priority in cancer therapy. To achieve this goal, we screened a compound library using a biochemical assay based on refolding of denatured firefly luciferase. The assay revealed high sensitivity, reliability and reproducibility with a Z-factor of 0.81±0.17. Six Hsp90 inhibitory compounds identified by this screening with IC50 values between 1.0 and 6μM were further characterised for anti-proliferative activity by Cell Titer-Blue Cell Viability Assay using multiple tumour cell lines. Of particular interest was ONO4140 with lowest GI50 values in three different cancer cell lines viz; DU-145, BT-474 and K562 cell lines. This study also revealed that short-term exposure of tumour cells with ONO4140 is sufficient to inhibit the catalytic activity of Hsp90, evaluated through disruption of Hsp90-p23 association by immunoprecipitation. This short term exposure appears to initiate events like degradation of Hsp90 client proteins such as ErbB2/Her-2 and Akt with concomitant inhibition of survival signalling leading to the apoptotic death of tumour cells as seen by western blotting and Caspase Glow-3,7 assay. The study also reveals that apoptosis following Hsp90 inhibition with ONO4140 occurs via Caspase9–Caspase3 intrinsic apoptotic pathway, a process that is likely triggered by inactivation of Akt. In conclusion, we have identified a novel class of synthetic compounds which show potent Hsp90 inhibitory action in preclinical studies. The discovery of this novel class of synthetic Hsp90 inhibitors with simple chemical backbone allows us to conduct further structural modifications to improve their potency and pharmacokinetic properties for use in cancer therapy.

From Anion Receptors to Transporters

Cystic fibrosis is the most well-known of a variety of diseases termed channelopathies, in which the regulation of ion transport across cell membranes is so disrupted that the threshold of a pathology is passed. The human toll exacted by these diseases has led a number of research groups, including our own, to create compounds that mediate ion transport across lipid bilayers. In this Account, we discuss three classes of synthetic compounds that were refined to bind and transport anions across lipid bilayer membranes. All of the compounds were originally designed as anion receptors, that is, species that would simply create stable complexes with anions, but were then further developed as transporters. By studying structurally simple systems and varying their properties to change the degree of preorganization, the affinity for anions, or the lipophilicity, we have begun to rationalize why particular anion transport mechanisms (cotransport or antiport processes) occur in particular cases. For example, we have studied the chloride transport properties of receptors based on the closely related structures of isophthalamide and pyridine-2,6-dicarboxamide: the central ring in each case was augmented with pendant methylimidazole groups designed to cotransport H(+) and Cl(-). We observed that the more preorganized pyridine-based receptor was the more efficient transporter, a finding replicated with a series of isophthalamides in which one contained hydroxyl groups designed to preorganize the receptor. This latter class of compound, together with the natural product prodigiosin, can transport bicarbonate (as part of a chloride/bicarbonate antiport process) across lipid bilayer membranes. We have also studied the membrane transport properties of calix[4]pyrroles. Although the parent meso-octamethylcalix[4]pyrrole functions solely as a Cs(+)/Cl(-) cotransporter, other compounds with increased anion affinities can function through an antiport process. One example is octafluoro-meso-octamethylcalix[4]pyrrole; with its electron-withdrawing substituents, it can operate through a chloride/bicarbonate antiport process. Moreover, calix[4]pyrroles with additional hydrogen bond donors can operate through a chloride/nitrate antiport process. Thus, increasing the affinity of the receptor in these cases allows the compound to transport an anion in the absence of a cation. Finally, we have studied the transport properties of simple thioureas and shown that these compounds are highly potent chloride/bicarbonate antiport agents that function at low concentrations. In contrast, the urea analogues are inactive. The higher hydrophobicity (reflected in higher values for the logarithm of the water-octanol partition constant, or log P) and lower polar surface areas of the thiourea compounds compared to their urea analogues may provide a clue to the high potency of these compounds. This observation might serve as a basis for designing future small-molecule transporters.

Hyperthermophilic phosphotriesterases/lactonases for the environment and human health

In the last decades the idea to use enzymes for environmental bioremediation has been more and more proposed and, in the light of this, new solutions have been suggested and detailed studies on some classes of enzymes have been performed. In particular, our attention in the last few years has been focused on the enzymes belonging to the amidohydrolase superfamily. Several members of this superfamily are endowed with promiscuous activities. The term ‘catalytic promiscuity’ describes the capability of an enzyme to catalyse different chemical reactions, called secondary activities, at the active site responsible for the main activity. Recently, a new family of microbial lactonases with promiscuous phosphotriesterase activity, dubbed PTE‐Like Lactonase (PLL), has been ascribed to the amidohydrolase superfamily. Among members of this family are enzymes found in the archaea Sulfolobus solfataricus and Sulfolobus acidocaldarius, which show high thermophilicity and thermal resistance. Enzymes showing phosphotriesterase activity are attractive from a biotechnological point of view because they are capable of hydrolysing the organophosphate phosphotriesters (OPs), a class of synthetic compounds employed worldwide both as insecticides and chemical warfare agents. Furthermore, from a basic point of view, studies of catalytic promiscuity offer clues to understand natural evolution of enzymes and to translate this into in vitro adaptation of enzymes to specific human needs. Thermostable enzymes able to hydrolyse OPs are considered good candidates for the set‐up of efficient detoxification tools.

Toxic effects of single-walled carbon nanotubes on the cardiovascular system: state of art

Engineered single-walled carbon nanotubes are a new class of synthetic compounds in the nanometric scale, with unusual chemical and physical characteristics, which make them a very promising material in different industrial and biomedical fields. Their use is predicted to increase exponentially in the next few years. Given their similarity to the ultrafine component of air pollution, there is concern for untoward effects on human health, especially in occupational and environmental settings. This review analyses the available findings on their possible toxicity on the cardiovascular system, a potential important target after human exposure. In particular, we have critically evaluated data on the possible pathophysiological pathways triggered by these particles.

Enzymes with Phosphotriesterase and Lactonase Activities in Archaea

Organophosphates (OPs) are a class of synthetic compounds used both as pesticides and nerve agents. They are chemically phosphoesters and biologically potent irreversible inhibitors of serine esterases, particularly acetylcholinesterase (ACh), the key enzyme of the nervous system. Enzymes able to degrade these compounds are at the moment the focus of several research studies in the environmental decontamination/detoxification field. OP hydrolysing enzymes have been found in Bacteria, Archaea and Eukarya. The best known and characterised enzyme is phosphotriesterase from the soil bacterium Pseudomonas diminuta (PTE). It shows a high catalytic activity, close to the molecular diffusion limit, against some triester organophosphates. Its natural substrate and its main physiological function are still unknown. In the last few years, two phosphotriesterase activities have been found in the hyperthermoacidophilic archaea Sulfolobus solfataricus and Sulfolobus acidocaldarius, which have been ascribed to two PTE-related genes (ssopox and sacpox). The corresponding proteins, SsoPox and SacPox, have recently been inserted in the Phosphotriesterase-Like-Lactonase (PLL) group. Their lactonase activity is around 100-fold higher than that of phosphotriesterase and it depends on the same active site. These enzymes are thermophilic and extremely thermostable. Stability in high temperatures and in other stressful conditions is an important feature for every biotechnological application in the industrial field. Finally, the lactonase activity would suggest a potential physiological role for SsoPox and SacPox in the quenching of signals involved in the pathways for cell-to-cell communication.

The potential of antidiabetic thiazolidinediones for anticancer therapy

The thiazolidinediones (TZDs) are a class of synthetic compounds for treatment of insulin-resistant Type 2 diabetes mellitus. TZDs are known activators of the peroxisome proliferator-activated receptor-γ (PPAR-γ), and exert their antidiabetic action largely through this nuclear receptor family. Moreover, increasing experimental evidences of PPAR-γ-independent effects are accumulating. Apart from the established metabolic actions, TZD treatment exerts additional biological effect such as control of cell growth, differentiation, motility and programmed cell death. In this context, considerable interest has focused on TZDs as potential chemopreventive agents in oncology; however, despite encouraging observation on the potential anticancer effect of these drugs in several in vitro experimental models, controversial results have been obtained with animal models and in pilot clinical trials. This review summarises the molecular mechanisms of the antineoplastic actions of TZDs and the relevance of these findings in human pathology and therapy.

Synthesis of a New Family of N‐Aryl Lactams Active on Chemesthesis and Taste

AbstractA new class of synthetic compounds with chemesthetic activity has been identified. They have been designed ex‐novo by structural similarity with known cooling compounds such as menthol, icilin and cyclic ketoenamines. 19 new derivatives have been obtained easily and in high yields by Goldberg arylation or lactam ring closure on the appropriate phenol or benzoic acid derivative. The synthetic procedures are suitable for gram‐scale preparation, and the products are stable and easy to purify. 17 new compounds were submitted to preliminary sensory evaluation, and 3 of them showed cooling activity and, in some cases, tingling sensation in the oral cavity. These N‐aryl lactams seem to be an interesting class of compounds to be enlarged in order to derive structure‐activity relationships. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Identification of novel subtype selective RAR agonists

Drugs targeting retinoid receptors have been developed to treat a variety of therapeutic indications, but their success has been limited in part due to lack of selectivity. A novel functional cell-based assay R-SAT™ was employed to screen a small molecule chemical library and identify a variety of novel RAR agonists with various subtype selectivities, including RARβ/γ and RARγ selective agonists. A novel class of synthetic compounds that distinguishes between the different RARβ isoforms is described. This pharmacophore displays anti-proliferative activity and induces differentiation in a neuronal cell line, consistent with a classical retinoid mechanism of action while providing unique subtype selectivity. These novel subtype selective RAR agonists could serve as powerful tools to probe into subtype and isoform-specific retinoid function.

Identification of Gene-selective Modulators of the Bile Acid Receptor FXR

BAR is a nuclear bile acid receptor (BAR) (FXR) receptor that regulates gene networks involved in cholesterol and bile acid homeostasis. We have identified two classes of synthetic compounds that differentially modulate BAR activity. The first class activates BAR target genes in the predicted fashion and is 25-fold more potent than endogenous bile acids. The second class, represented by AGN34, antagonizes BAR in transient reporter assays. Surprisingly, this compound acts in a gene-selective manner in vivo: it is an agonist on CYP7A1, an antagonist on IBABP, and is neutral on SHP. These findings indicate that synthetic BAR modulators can be developed to regulate transcription in a gene-specific fashion. Given the ability of BAR to regulate several lipid homeostatic pathways, the identification of gene-selective BAR modulators have important implications for the development of improved cholesterol lowering agents.

Apocalypse soon?

Apocalypse soon?

Interactions of synthetic estrogens with human estrogen receptors

Synthetic estrogens have diverse chemical structures and may either positively or negatively affect the estrogenic signaling pathways through interactions with the estrogen receptors (ERs). Modeling studies suggest that 4-(1-adamantyl)phenol (AdP) and 4,4'-(1,3-adamantanediyl)diphenol (AdDP) can bind in the ligand binding site of ERalpha. We used fluorescence polarization (FP) to compare the binding affinities of AdP, AdDP and 2-(1-adamantyl)-4-methylphenol (AdMP) for human ERalpha and ERbeta with the binding affinities of the known ER ligands, diethylstilbestrol (DES) and 4hydroxytamoxifen (4OHT). Competition binding experiments show that AdDP has greater affinity for both ERs than does AdP, while AdMP does not bind the receptor proteins. The relative binding affinities of AdDP and AdP are weaker than the affinity of DES or 4OHT for both ERs with the exception of AdDP, which binds ERbeta with higher affinity than does 4OHT. We also found that AdDP and AdP cause differential conformational changes in ERalpha and ERbeta, which result in altered affinities of the ERs for fluorescein-labeled estrogen response elements (EREs) using a direct binding FP assay. The results show that ERbeta liganded with either AdDP or AdP has greater affinity for human pS2 ERE than the ERbeta-4OHT complex. The data suggest that synthetic molecules like adamantanes may function as biologically active ligands for human ERs. This demonstrates the importance of considering the potential of novel classes of synthetic compounds as selective ER modulators.