Regioselective synthesis, physicochemical properties and anticancer activity of 2-aminomethylated estrone derivatives

The unique estrogen receptor (ER)-independent antiproliferative and apoptotic activity of 2-methoxyestradiol (2ME2) is well known, however, its use has been limited because of its poor oral bioavailability. In this study, novel 2-aminomethylated estrone (E) and estradiol (E2) derivatives structurally related to 2ME2 were synthesized, and their physicochemical properties as well as their in vitro cytotoxic effects were investigated in the hope to find more selective antiproliferative agents with improved pharmacokinetic profile. The target compounds were synthesized from 2-dimethylaminomethylated E obtained regioselectively by a three-component Mannich reaction. Quaternization with methyl iodide followed by reacting the ammonium salt with various dialkyl and alicyclic secondary amines afforded the desired products in good yields.
The reactions proceeded via a 1,4-nucleophilic addition of the applied secondary amines to the ortho-quinone methide (o-QM) intermediates, generated in situ from the salt by base-promoted β-elimination. The compound library has been enlarged with structurally similar E2 analogues obtained by stereoselective reduction and with some 17β-benzylamino derivatives prepared by reductive amination. The potential values of the novel E and E2 derivatives were characterised by means of three different approaches. At the first step compounds were virtually screened using physicochemical parameters. Physicochemical characterization was completed by kinetic solubility and in vitro intestinal-specific permeability measurement. Antiproliferative effects were additionally determined on a panel of malignant and non-cancerous cell lines. The evaluation of the pharmacological profile of the novel E and E2 derivatives was completed with the calculation of lipophilic efficacy (LiPE).

The Role of Estriol and Estrone in Keratoconic Stromal Sex Hormone Receptors

Keratoconus (KC) is a progressive corneal thinning disease that manifests in puberty and worsens during pregnancy. KC onset and progression are attributed to diverse factors that include: environmental, genetics, and hormonal imbalances; however, the pathobiology remains elusive. This study aims to determine the role of corneal stroma sex hormone receptors in KC and their interplay with estrone (E1) and estriol (E3) using our established 3D in vitro model. Healthy cornea stromal cells (HCFs) and KC cornea stromal cells (HKCs), both male and female, were stimulated with various concentrations of E1 and E3.
Significant changes were observed between cell types, as well as between males and females in the sex hormone receptors tested; androgen receptor (AR), progesterone receptor (PR), estrogen receptor alpha (ERα), and estrogen receptor beta (ERβ) using Western blot analysis. E1 and E3 stimulations in HCF females showed AR, PR, and ERβ were significantly upregulated compared to HCF males. In contrast, ERα and ERβ had significantly higher expression in HKC’s females than HKC’s males. Our data suggest that the human cornea is a sex-dependent, hormone-responsive tissue that is significantly influenced by E1 and E3. Therefore, it is plausible that E1, E3, and sex hormone receptors are involved in the KC pathobiology, warranting further investigation.

Algorithms with Area under the Curve for Daily Urinary Estrone-3-Glucuronide and Pregnanediol-3-Glucuronide to Signal the Transition to the Luteal Phase

Background and Objectives: Home fertility assessment methods (FAMs) for natural family planning (NFP) have technically evolved with the objective metrics of urinary luteinizing hormone (LH), estrone-3-glucuronide (E3G) and pregnanediol-3-glucuronide (PDG). Practical and reliable algorithms for timing the phase of cycle based upon E3G and PDG levels are mostly unpublished and still lacking. Materials and Methods: A novel formulation to signal the transition to the luteal phase was discovered, tested, and developed with a data set of daily E3G and PDG levels from 25 women, 78 cycles, indexed to putative ovulation (day after the urinary LH surge), Day 0. The algorithm is based upon a daily relative progressive change in the ratio, E3G-AUC/PDG-AUC, where E3G-AUC and PDG-AUC are the area under the curve for E3G and PDG, respectively.
To improve accuracy the algorithm incorporated a three-fold cycle-specific increase of PDG. Results: An extended negative change in E3G-AUC/PDG-AUC of at least nine consecutive days provided a strong signal for timing the luteal phase. The algorithm correctly identified the luteal transition interval in 78/78 cycles and predicted the start day of the safe period as: Day + 2 in 10/78 cycles, Day + 3 in 21/78 cycles, Day + 4 in 28/78 cycles, Day + 5 in 15/78 cycles, and Day + 6 in 4/78 cycles. The mean number of safe luteal days with this algorithm was 10.3 ± 1.3 (SD). Conclusions: An algorithm based upon the ratio of the area under the curve for daily E3G and PDG levels along with a relative PDG increase offers another approach to time the phase of cycle. This may have applications for NFP/FAMs and clinical evaluation of ovarian function.

The 3-oxoacyl-(acyl-carrier-protein) reductase HSD-X1 of Pseudomonas citronellolis SJTE-3 catalyzes the conversion of 17β-estradiol to estrone

Background: Pseudomonas citronellolis SJTE-3 can efficiently degrade 17β-estradiol (E2) and other estrogenic chemicals. However, the enzyme responsible for E2 metabolism within strain SJTE-3 has remained unidentified.
Objective: Here, a novel 3-oxoacyl-(acyl-carrier protein) (ACP) reductase, HSD-X1 (WP_009617962.1), was identified in SJTE-3 and its enzymatic characteristics for the transformation of E2 were investigated.
Methods: Multiple sequence alignment and homology modelling were used to predict the protein structure of HSD-X1. The concentrations of different steroids in the culture of recombinant strains expressing HSD-X1 were determined by high performance liquid chromatography. Additionally, the transcription of hsd-x1 gene was investigated using reverse transcription and quantitative PCR analysis. Heterologous expression and affinity purification were used to obtain recombinant HSD-X1.
Results: The transcription of hsd-x1 gene in P. citronellolis SJTE-3 was induced by E2. Multiple sequence alignment (MSA) indicated that HSD-X1 contained the two consensus regions and conserved residues of short-chain dehydrogenase/reductases (SDRs) and 17β-hydroxysteroid dehydrogenases (17β-HSDs). Over-expression of hsd-x1 gene allowed the recombinant strain to degrade E2. Recombinant HSD-X1 was purified with a yield of 22.15 mg/L and used NAD+ as its cofactor to catalyze the oxidization of E2 into estrone (E1), while exhibiting a Km value of 0.025 ± 0.044 mM and a Vmax value of 4.92 ± 0.31 mM/min/mg. HSD-X1 could tolerate a wide range of temperature and pH, while the presence of divalent ions exerted little influence on its activity. Further, the transformation efficiency of E2 into E1 was over 98.03% across 15 min.
Conclusion: Protein HSD-X1 efficiently catalyzed the oxidization of E2 and participated in estrogen degradation by P. citronellolis SJTE-3.

Estrone(Estrone) ELISA Kit

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Estrone(Estrone) ELISA Kit

EKF57997-48T Biomatik Corporation 48T 396.9 EUR

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Temporal compositional shifts in an activated sludge microbiome during estrone biodegradation

  • Microbial biodegradation is a key process for the removal of estrogens during wastewater treatment. At least four degradation pathways for natural estrogens have been proposed. However, major estrogen degraders and the occurrence of different estrogen biodegradation pathways in wastewater treatment plants have been rarely investigated. This study was conducted to elucidate estrone biodegradation pathway and to identify key estrone-degrading bacteria in activated sludge from a major wastewater treatment plant in Bahrain. The biodegradation experiments were performed in activated sludge microcosms supplemented with estrone. Sludge samples were retrieved at time intervals to analyze the biodegradation metabolites and the temporal shifts in the bacterial community composition.
  • Chemical analysis revealed the biodegradation of more than 90% of the added estrone within 6 days, and the compounds 4-hydroxyestrone and pyridinestrone acid, which are typical markers of the 4,5-seco pathway of aerobic estrone biodegradation, were detected. Temporal shifts in the relative abundance of bacteria were most prominent among members of Proteobacteria and Bacteroidetes. While the alphaproteobacterial genera Novosphingobium and Sphingoaurantiacus were significantly enriched (from ≤ 6% to an average of 31%) in the estrone-amended activated sludge after 2 days of incubation, the bacteroidete Pedobacter was uniquely detected in these microcosms at day 10. The relative abundance of Polyangia (Nannocyctis) increased to an average of 10 ± 0.4% in the estrone-amended activated sludge after 4 days of incubation.
  • Enrichment cultivation of bacteria from the activated sludge on estrone resulted in a mixed culture that was capable of degrading estrone. An estrone-degrading strain was isolated from this mixed culture and was affiliated with the known estrogen-degrading Alphaproteobacteria Sphingobium estrogenivorans. We conclude that estrone degradation in the activated sludge from the studied wastewater treatment plant proceeds via the 4,5-seco pathway and is most likely mediated by alphaproteobacterial taxa.