-
European Journal of Medicinal Chemistry Feb 2020The aminosteroid (AM) RM-581 is built around a mestranol backbone and has recently emerged as this family's lead candidate, showing in vitro and in vivo potency over...
The aminosteroid (AM) RM-581 is built around a mestranol backbone and has recently emerged as this family's lead candidate, showing in vitro and in vivo potency over different types of cancer, including high fatality pancreatic cancer. To extend the structure-activity relationships (SAR) to other estrane analogs, we synthesized a focused series of RM-581 derivatives at position C3 or C2 of its steroidal core. These new AM derivatives were first tested on a large selection of prostate, breast, pancreatic and ovarian cancer cell lines. The impact of these modifications on metabolic stability (human liver microsomes) was also measured. A SAR study revealed a fine regulation of anticancer activity related to the nature of the substituent. Indeed, the addition of potential prodrug groups like acetate, sulfamate or phosphate (compounds 8, 9 and 10) at C3 of the phenolic counterpart provided better antiproliferative activities than RM-581 in breast and pancreatic cancer cell types while maintaining activity in other cancer cell lines. Also, the phosphate group was highly beneficial on water solubility. However, the bulkier carbamate prodrugs 6 (N,N-dimethyl) and 7 (N,N-diethyl) were less active. Otherwise, carbon homologation (CH) at C2 (compound 33) was beneficial to metabolic stability and, in the meantime, this AM conserved the same anticancer activity as RM-581. However, the replacement of the hydroxy or methoxy at C3 by a hydrogen or an acetyl (compound 17 or 21b) was detrimental for anticancer activity, pointing to a crucial molecular interaction of the aromatic oxygen atom at this position. Overall, this work provided a better knowledge of the structural requirements to maintain RM-581's anticancer activity, and also identified minor structural modifications to increase both metabolic stability and water solubility, three important parameters of pharmacological development.
Topics: Antineoplastic Agents; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Estranes; Humans; Liver; Molecular Structure; Solubility; Structure-Activity Relationship; Tumor Cells, Cultured; Water
PubMed: 31893547
DOI: 10.1016/j.ejmech.2019.111990 -
Chemosphere Feb 2017To analyze polymeric nanosorbents and nanofiltration/ultrafiltration membranes for hormone micropollutants removal from water effluents, here an in-through investigation...
An enquiry on appropriate selection of polymers for preparation of polymeric nanosorbents and nanofiltration/ultrafiltration membranes for hormone micropollutants removal from water effluents.
To analyze polymeric nanosorbents and nanofiltration/ultrafiltration membranes for hormone micropollutants removal from water effluents, here an in-through investigation on the suitability and compatibility of various polymers has been carried out. For this work, estradiol, estrone, testosterone, progesterone, estriol, mestranol, and ethinylestradiol were considered. A total number of 452 polymers were analyzed and initially screened using Hansen solubility parameters. The identified good pairs of hormones and polymers then were examined to obtain the equilibrium capacity of hormones removal from water effluents using a modified Flory-Huggins model. A distribution coefficient was defined as the ratio of hormones in water effluent phase and polymer phase. For removal of mestranol, estradiol and ethinylestradiol, no compatible polymer was identified based on initial screening of collected database. Three compatible polymers were identified for estriol. For progesterone, a wide variety of polymers was identified as good matching of polar, dispersion and hydrogen forces contributions can be observed for these pairs. For estrone, only two polymers can be proposed due to the mismatch observed between polar, dispersion and hydrogen forces contributions of other polymers and this hormone. The phase calculations showed that not all the identified good pairs could be used for practical separation applications. The domain of applicability of each good pair was investigated and potential polymers for practical micropollutants removal together with their removal capacity were represented in terms of phase envelops. The theoretical approach follows fundamental chemical thermodynamic equations and then can be simply applied for any system of interest.
Topics: Adsorption; Hormones; Membranes, Artificial; Models, Theoretical; Nanostructures; Polymers; Solubility; Thermodynamics; Ultrafiltration; Water Pollutants, Chemical; Water Purification
PubMed: 27776242
DOI: 10.1016/j.chemosphere.2016.10.049 -
Journal of the Indian Society of... 2018Plaque removal is of utmost importance for control of dental caries and other associated diseases of oral cavity. However, various natural agents have proven their...
INTRODUCTION
Plaque removal is of utmost importance for control of dental caries and other associated diseases of oral cavity. However, various natural agents have proven their efficacy over chemotherapeutic agents in terms of antibacterial activity against various microorganisms. The effect is mainly due to polyphenol as its major constituent.
AIM
In this in vitro study, we aimed to determine the antibacterial efficacy of Trachyspermum ammi oil at different concentrations against five oral bacteria.
HYPOTHESIS
Herbal compound, T. ammi oil is effective in reducing five oral plaque-forming bacteria.
MATERIALS AND METHODS
We determined the antimicrobial activity of T. ammi oil (test material) against chlorhexidine (gold standard). Pure cultures of Streptococcus mutans MTCC No 497, Streptococcus oralis MTCC No. 2696, Lactobacillus acidophilus MTCC No. 10307, Lactobacillus fermentum MTCC No. 903, and Candida albicans MTCC No. 183 were obtained and grown in selective culture media. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of both materials were evaluated by serial dilution and disc diffusion method, respectively.
RESULTS
Our results revealed that T. ammi oil moderately inhibits bacterial growth with mean MIC of 250, 125, 250, 125, and 250 μg/ml, respectively. Mean MBC for T. ammi oil obtained was 18.60 ± 0.65, 11.60 ± 1.14, 14.10 ± 0.55, 11.50 ± 0.61, and 15.10 ± 0.74 mm. The MIC and MBC values were higher as compared to chlorhexidine gluconate and it was statistically significant.
CONCLUSION
T. ammi (ajwain) can serve as a potential, natural, nontoxic, and economical therapeutic antiplaque agent.
Topics: Anti-Bacterial Agents; Anti-Infective Agents, Local; Chlorhexidine; Chlormadinone Acetate; In Vitro Techniques; Mestranol; Microbial Sensitivity Tests; Mouth; Spiro Compounds
PubMed: 30324925
DOI: 10.4103/JISPPD.JISPPD_65_18 -
Journal of the American Chemical Society Feb 2019Crystals of molecular rotor 1 with a central 1,4-phenylene rotator linked to two molecules of the steroid mestranol were prepared with 1%, 5%, 20%, and up to 40% of the...
Crystals of molecular rotor 1 with a central 1,4-phenylene rotator linked to two molecules of the steroid mestranol were prepared with 1%, 5%, 20%, and up to 40% of the analogous 2, which contains a larger 2,3-difluorophenylene rotator and effectively acts as a monkey wrench that affects the rotation of the host. The packing motif of the desired P3 crystal form consists of 1D columns of nested rotors arranged in helical arrays with the central aromatic rotators disordered over two sites related by 85° rotation about their 1,4-axes. Rotational dynamics measured by quadrupolar echo H NMR line shape analysis were analyzed in terms of a process model that involves degenerate 180° jumps in the fast exchange regime combined with a highly correlated and entropically demanding jump of 85° between the two dynamically disordered sites. While the enthalpic and entropic barriers for the 180° jump estimated from H T measurements were Δ H = 2.7 ± 0.1 kcal mol and Δ S = -5.0 ± 0.5 cal mol K, respectively, the corresponding parameters for the slower 85° jumps, determined by line shape analysis, were Δ H = 2.2 kcal mol and Δ S = -23 cal mol K. Increasing amounts of the larger molecular rotor 2 in the solid solution results in significant dynamic perturbations as the guest, acting as a monkey wrench, reaches values of one out of every five molecular rotors in the chain.
PubMed: 30620195
DOI: 10.1021/jacs.8b11385 -
Organic Letters Aug 2016An efficient and transition-metal-free method is presented to access tertiary alkyl aryl ethers by arylation of tertiary alcohols with ortho-substituted diaryliodonium...
An efficient and transition-metal-free method is presented to access tertiary alkyl aryl ethers by arylation of tertiary alcohols with ortho-substituted diaryliodonium salts. The scope covers cyclic and acyclic aliphatic, benzylic, allylic, and propargylic tertiary alcohols as well as primary and secondary fluorinated alcohols. The methodology gives access to alkyl aryl ethers of previously unprecedented steric congestion. Furthermore, the versatility of the developed procedure was demonstrated by arylation of the pro-drug mestranol.
PubMed: 27529124
DOI: No ID Found -
Journal of Separation Science Feb 2016The development of a simple and sensitive analytical approach that combines multiple monolithic fiber solid-phase microextraction with liquid desorption followed by...
Multiple monolithic fiber solid-phase microextraction based on a polymeric ionic liquid with high-performance liquid chromatography for the determination of steroid sex hormones in water and urine.
The development of a simple and sensitive analytical approach that combines multiple monolithic fiber solid-phase microextraction with liquid desorption followed by high-performance liquid chromatography with diode array detection is proposed for the determination of trace levels of seven steroid sex hormones (estriol, 17β-estradiol, testosterone, ethinylestradiol, estrone, progesterone and mestranol) in water and urine matrices. To extract the target analytes effectively, multiple monolithic fiber solid-phase microextraction based on a polymeric ionic liquid was used to concentrate hormones. Several key extraction parameters including desorption solvent, extraction and desorption time, pH value and ionic strength in sample matrix were investigated in detail. Under the optimal experimental conditions, the limits of detection were found to be in the range of 0.027-0.12 μg/L. The linear range was 0.10-200 μg/L for 17β-estradiol, 0.25-200 μg/L estriol, ethinylestradiol and estrone, and 0.50-200 μg/L for the other hormones. Satisfactory linearities were achieved for analytes with the correlation coefficients above 0.99. Acceptable method reproducibility was achieved by evaluating the repeatability and intermediate precision with relative standard deviations of both less than 8%. The enrichment factors ranged from 54- to 74-fold. Finally, the proposed method was successfully applied to the analysis of steroid sex hormones in environmental water samples and human urines with spiking recoveries ranged from 75.6 to 116%.
Topics: Chromatography, High Pressure Liquid; Gonadal Steroid Hormones; Hydrogen-Ion Concentration; Ionic Liquids; Limit of Detection; Osmolar Concentration; Solid Phase Microextraction; Water Pollutants
PubMed: 26608868
DOI: 10.1002/jssc.201501156 -
Environmental Pollution (Barking, Essex... Apr 2016Phenolic endocrine disrupting chemicals (EDCs) in an estuarine water column in a depth profile of five water layers (0.05 D, 0.20 D, 0.60 D, 0.80 D and 0.90 D, D =...
Phenolic endocrine disrupting chemicals (EDCs) in an estuarine water column in a depth profile of five water layers (0.05 D, 0.20 D, 0.60 D, 0.80 D and 0.90 D, D = Depth, 10.7 ± 0.7 m) and their corresponding environmental parameters (tide, salinity and particle size) were investigated over a year. Water sample from each layer was further separated into three fractions, which were dissolved, coarse (SPM-D, Φ ≥ 2.7 μm) and fine (SPM-F, 2.7 μm > Φ ≥ 0.7 μm) suspended particulate matters. Most of EDCs in the water column were presented in the dissolved fraction. Vertical profiles of salinity fluctuations showed that the upper water layer was most influenced by upstream flow. Estriol (E3), mestranol (Mes) and 17α-ethynylestradiol (EE2) concentrations were significantly higher in ebb tide than in flood tide, indicating that EDCs mainly came from terrestrial source, the upstream flow. Dissolved EDCs also exhibited high levels in the surface layer (0.05 D) due to the upstream source and atmosphere deposition, followed by the bottom layer (0.90 D) owing to the re-suspension of EDCs-containing sediment. Compared to the dissolved phase, the contents of BPA, Mes and EE2 in the solid phase were affected by particle size and exhibited a trend of SPM-F > SPM-D > sediment. On the other hand, the concentrations of octylphenol (OP) and t-nonylphenol (NP), the degradation products from common nonionic surfactants, in sediment were higher than those in suspended particles, and NP concentration was higher in flood tide than that in ebb tide. For both SPM-D and SPM-F, their corresponding EDCs concentrations were negatively related to SPM concentrations due to particle concentration effect (PCE). Owing to the "salting-out effect", salinity pushed EDCs from dissolved fraction to particulate or sedimentary phase.
Topics: Endocrine Disruptors; Environmental Monitoring; Estriol; Ethinyl Estradiol; Floods; Particle Size; Particulate Matter; Phenols; Rivers; Salinity; Seawater; Water Pollutants, Chemical
PubMed: 26736056
DOI: 10.1016/j.envpol.2015.12.034 -
Chemosphere Jul 2017This paper is devoted to investigate the suitability of cellulose for estrogens micropollutants removal from water effluent. For this purpose, the sorption of eight...
This paper is devoted to investigate the suitability of cellulose for estrogens micropollutants removal from water effluent. For this purpose, the sorption of eight estrogens including Estradiol, Estrone, Testosterone, Progesterone, Estriol, Mestranol, Ethinylestradiol and Diethylstilbestrol were investigated. The charge density profiles and sorption curves were obtained and discussed using quantum chemical calculations where the Accelrys Materials Studio software and COSMO-SAC model were employed. The geometry optimization of compound molecule and energy minimizations was performed using the Dmol3 Module and density functional theory of generalized gradient approximate and Volsko-Wilk-Nusair functional. We found that cellulose cannot be a reliable choice of sorbent for removal of Estrone and Estradiol, but it is a poor choice of sorbent for removal of Estriol, Ethinylestradiol. Cellulose can be used for Diethylstilbestrol, Mestranol, Testosterone and Progesterone removal from estrogens containing effluents.
Topics: Cellulose; Estrogens; Models, Chemical; Quantum Theory; Waste Disposal, Fluid; Water Pollutants, Chemical
PubMed: 28342373
DOI: 10.1016/j.chemosphere.2017.02.152 -
Journal of the American Chemical Society Feb 2015A molecular rotor built with a stator formed by two rigid 9β-mestranol units having a 90° bent angle linked to a central phenylene rotator has an ideal structure to...
A molecular rotor built with a stator formed by two rigid 9β-mestranol units having a 90° bent angle linked to a central phenylene rotator has an ideal structure to examine aromatic CH/π interactions. Energies and populations of the multiple solution conformations from quantum-mechanical calculations and molecular dynamics simulations were combined with variable-temperature (VT) (1)H NMR data to establish the enthalpy of this interaction and the entropy associated with rotation about a single bond. Rotational dynamics in the solid state were determined via VT cross-polarization magic-angle spinning (13)C NMR spectroscopy.
PubMed: 25635355
DOI: 10.1021/ja512053t