7249-00-5Relevant academic research and scientific papers
Regioselective synthesis, physicochemical properties and anticancer activity of 2-aminomethylated estrone derivatives
Kinyua, Njangiru Isaac,Balogh, Gy?rgy T.,Frank, éva,Leits, Péter,Mótyán, Gerg?,Minorics, Renáta,Molnár, Barnabás,Zupkó, István
, (2022/02/05)
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 of finding 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).
Synthesis, estrogen receptor binding affinity and biological evaluation of some 2-substituted estrone derivatives
Omar,Aboulwafa,Labouta,El-Tombary,El-Mallah
, p. 219 - 225 (2007/10/03)
This report details the preparation of modified estrogens which are structurally designed to possess estrogenic and/or antiestrogenic activity. The prominent feature of these estrogens is the introduction of a novel side chain in the 2-position of ring A of the steroid nucleus. Their synthesis includes the use of transformations based upon Mannich base chemistry: preparation of the intermediate 2-dimethylaminomethylestrone via aminomethylation of estrone and introduction of various functionalities via reaction of this Mannich base with different reagents. When evaluated for their interaction with the estrogen receptor by competitive binding assays, the tested products were found to be relatively weak competitors at 0 °C. The uterotrophic and post-coital antifertility assays indicated effects varying in magnitude relative to estradiol. Ethyl[(2'-acetyl 3'-(3- hydroxyestra-17-oxo-1,3,5(10)-trien-2-yl)]propionate (15) showed uterotrophic and antiimplantation activities of 95% and 20% respectively.
