362-08-3Relevant articles and documents
A-ring-substituted estrogen-3-O-sulfamates: Potent multitargeted anticancer agents
Leese, Mathew P.,Hejaz, Hatem A. M.,Mahon, Mary F.,Newman, Simon P.,Purohit, Atul,Reed, Michael J.,Potter, Barry V. L.
, p. 5243 - 5256 (2005)
Efficient and flexible syntheses of 2-substituted estrone, estradiol and their 3-O-sulfamate (EMATE) derivatives have been developed using directed ortho-lithiation methodology. 2-Substituted EMATEs display a similar antiproliferative activity profile to the corresponding estradiols against a range of human cancer cell lines. 2-Methoxy (3, 4), 2-methylsulfanyl (20, 21) and 2-ethyl EMATEs (32, 33) proved the most active compounds with 2-ethylestradiol-3-O-sulfamate (33), displaying a mean activity over the NCI 55 cell line panel 80-fold greater than the established anticancer agent 2-methoxyestradiol (2). 2-Ethylestradiol-3-O-sulfamate (33) was also an effective inhibitor of angiogenesis using three in vitro markers, and various 2-substituted EMATEs also proved to be inhibitors of steroid sulfatase (STS), a therapeutic target for the treatment of hormone-dependent breast cancer. The potential of this novel class of multimechanism anticancer agents was confirmed in vivo with good activity observed in the NCI hollow fiber assay and in a MDA-MB-435 xenograft mouse model.
Synthesis and biological evaluations of new analogs of 2-methoxyestradiol: Inhibitors of tubulin and angiogenesis
Solum, Eirik Johansson,Cheng, Jing-Jy,S?rvik, Irene B.,Paulsen, Ragnhild E.,Vik, Anders,Hansen, Trond Vidar
, p. 391 - 398 (2014)
The synthesis, cytotoxicity, inhibition of tubulin polymerization and anti-angiogenic effects of 15 analogs of 2-methoxyestradiol (1) are reported. The biological studies revealed that the position of nitrogen atom in the heterocyclic ring is important for inhibition of both tubulin polymerization and angiogenesis. The most potent inhibitors were compounds 11f and 13e, with a 6-substituted isoquinoline ring in the 17-position of the steroid skeleton. Moreover, low estrogen activity was observed for the analogs tested at 10 μM concentrations.
Discovery of chalcone-modified estradiol analogs as antitumour agents that Inhibit tumour angiogenesis and epithelial to mesenchymal transition
Wang, Cong,Li, Leilei,Fu, Dongyang,Qin, Tiantian,Ran, Yange,Xu, Feng,Du, Xinrui,Gao, Haiying,Sun, Shuaijun,Yang, Tengjiao,Zhang, Xueyan,Huo, Junfeng,Zhao, Wen,Zhang, Zhenzhong,Shi, Xiufang
, p. 135 - 148 (2019)
Angiogenesis plays an essential role in tumourigenesis and tumour progression, and anti-angiogenesis therapies have shown promising antitumour effects in solid tumours. 2-Methoxyestradiol (2ME2), an endogenous metabolite of estradiol, has been regarded as a potential antitumour agent mainly targeting angiogenesis. Here we synthesized a novel series of chalcones based on 2-methoxyestradiol and evaluated their potential activities against tumours. Compound 11e was demonstrated to have potent antiangiogenic activity. Further studies showed that 11e suppressed tumour growth in human breast cancer (MCF-7)xenograft models without obvious side effects. Evaluation of the mechanism revealed that 11e targeted the epithelial to mesenchymal transition (EMT)process in MCF-7 cells and inhibited HUVEC migration and then contributed to hindrance of angiogenesis. Thus, 11e may be a promising antitumour agent with excellent efficacy and low toxicity.
Synthesis and antitumor activities of 3-modified 2-methoxyestradiol analogs
Suwandi, Lita S.,Agoston, Gregory E.,Shah, Jamshed H.,Hanson, Arthur D.,Zhan, Xiaoguo H.,LaVallee, Theresa M.,Treston, Anthony M.
, p. 6459 - 6462 (2009)
The syntheses of 2-methoxyestradiol analogs with modifications at the 3-position are described. The analogs were assessed for their antiproliferative, antiangiogenic, and estrogenic activities. Several lead substituents were identified with similar or imp
Synthesis and antimitotic activity of novel 2-methoxyestradiol analogs. Part III
Rao, Pemmaraju N.,Cessac, James W.,Boyd, James W.,Hanson, Arthur D.,Shah, Jamshed
, p. 171 - 183 (2008)
The syntheses and antimitotic activity of several novel analogs of 2-methoxyestradiol are described. Structural modifications include ring-D homologation, aromatization of the six-membered ring-D to a chrysine type molecule, and introduction of unsaturation in five-membered ring-D along with substitution of alkyl and ethynyl groups for the 17β-hydroxy function. Of nine analogs synthesized, five have demonstrated superior antiproliferative activities compared to 2-methoxyestradiol.
Synthesis, molecular modeling and biological evaluation of potent analogs of 2-methoxyestradiol
al-Kazaale, Nora,Tran, Phuong T.,Haidari, Farhad,Solum, Eirik Johansson,Liekens, Sandra,Vervaeke, Peter,Sylte, Ingebrigt,Cheng, Jing-Jy,Vik, Anders,Hansen, Trond Vidar
, p. 47 - 55 (2018/05/24)
The endogenous steroid 2-methoxyestradiol (1) has attracted a great interest as a lead compound towards the development of new anti-cancer drugs. Herein, the synthesis, molecular modeling, anti-proliferative and anti-angiogenic effects of ten 2-ethyl and four 2-methoxy analogs of estradiol are reported. The ethyl group was introduced to the steroid A-ring using a novel Friedel-Crafts alkylation protocol. Several analogs displayed potent anti-proliferative activity with IC50-values in the submicromolar range towards the CEM human leukemia cancer cell line. As such, all of these compounds proved to be more active than the lead compound 2-methoxyestradiol (1) in these cells. The six most cytostatic analogs were also tested as anti-angiogenic agents using an in vitro tube formation assay. The IC50-values were determined to be in the range of 0.1 μM ± 0.03 and 1.1 μM ± 0.2. These six compounds were also modest inhibitors against tubulin polymerization with the most potent inhibitor was 14b (IC50 = 2.1 ± 0.1 μM). Binding studies using N,N′-ethylene-bis(iodoacetamide) revealed that neither14a or 14b binds to the colchicine binding site in the tubulin protein, in contrast to 2-methoxyestradiol (1). These observations were supported by molecular modeling studies. Results from a MDA-MB-231 cell cycle assay showed that both 10e and 14b gave accumulation in the G2/M phase resulting in induction of apoptosis. The results presented herein shows that the novel analogs reported exhibit their anticancer effects via several modes of action.
For female steroid nucleus to 2 bit or 16 substituted chalcone derivative and its preparation and use
-
, (2017/08/26)
The invention belongs to the field of medicinal chemicals, and relates to a 2/16-site-substituted chalcone derivative taking estrogen as a mother nucleus and a preparation method and application of the derivative. The preparation method comprises the following step: combining chalcone structural fragments on an estrogen body in parallel, thereby keeping or improving the activity of anti-tumor cells and inhibiting activity of tumor cell angiogenesis. The structural formula of the 2/16-site-substituted chalcone derivative is as shown in the specification. The in-vitro anti-tumor cell proliferation activity test and the chick embryo allantois test show that the derivative has certain anti-tumor cell proliferation activity and inhibiting activity of tumor cell angiogenesis; and the dose-effect relationship study shows that the tumor cell inhibition function of the derivative is prior to that of 2-methoxy estradiol with broad-spectrum anti-tumor activity, and moreover the half-life period can be prolonged.
Continuous Production of Biorenewable, Polymer-Grade Lactone Monomers through Sn-Β-Catalyzed Baeyer–Villiger Oxidation with H2O2
Yakabi, Keiko,Mathieux, Thibault,Milne, Kirstie,López-Vidal, Eva M.,Buchard, Antoine,Hammond, Ceri
, p. 3652 - 3659 (2017/09/13)
The Baeyer–Villiger oxidation is a key transformation for sustainable chemical synthesis, especially when H2O2 and solid materials are employed as oxidant and catalyst, respectively. 4-substituted cycloketones, which are readily available from renewables, present excellent platforms for Baeyer–Villiger upgrading. Such substrates exhibit substantially higher levels of activity and produce lactones at higher levels of lactone selectivity at all values of substrate conversion, relative to non-substituted cyclohexanone. For 4-isopropyl cyclohexanone, which is readily available from β-pinene, continuous upgrading was evaluated in a plug-flow reactor. Excellent selectivity (85 % at 65 % conversion), stability, and productivity were observed over 56 h, with over 1000 turnovers (mol product per mol Sn) being achieved with no loss of activity. A maximum space–time yield that was almost twice that for non-substituted cyclohexanone was also obtained for this substrate [1173 vs. 607 g(product) kg(catalyst)?1 cm?3 h?1]. The lactone produced is also shown to be of suitable quality for ring opening polymerization. In addition to demonstrating the viability of the Sn-β/H2O2 system to produce renewable lactone monomers suitable for polymer applications, the substituted alkyl cyclohexanones studied also help to elucidate steric, electronic, and thermodynamic elements of this transformation in greater detail than previously achieved.
Preparation and Catalytic Property of Multi-walled Carbon Nanotubes Supported Keggin-Typed Tungstosilicic Acid for the Baeyer-Villiger Oxidation of Ketones
Yang, Zhiwang,Xu, Xueqing,Li, Tianjing,Zhang, Nana,Zhao, Xia,Chen, Wenlong,Liang, Xixi,He, Xinli,Ma, Hengchang
, p. 1955 - 1960 (2015/12/24)
Multi-walled carbon nanotubes (MWCNTs) supported HSiW/MWCNTs was successfully prepared and characterized by Fourier transform infrared spectoscopy, X-ray powder diffraction, transmission electron microscopy and N2 adsorption-desorption test. Its catalytic performance for the catalytic Baeyer-Villiger oxidation of cyclic ketones with 30 % H2O2 as oxidants was investigated. It was found that HSiW/MWCNTs was very efficient to transform of some cycloketones to the corresponding lactones with high conversions as well as selectivities. Factors affecting the oxidations and the reusability of the catalyst were also investigated. It was found that the catalyst can be reused seven times in the catalytic oxidation reaction of cyclopentanone without obviously catalytic activity losing in the oxidation. Graphical Abstract: A supported solid acid of HSiW/MWCNTs was used as efficient catalyst for the Baeyer-Villiger oxidation of ketones. High cyclopentanone conversion (98 %) and ε- valerolactone selectivity (99 %) were obtained. The catalyst can be reused at least seven runs in the oxidation of cyclopentanone.
Synthesis, cytotoxic effects and tubulin polymerization inhibition of 1,4-disubstituted 1,2,3-triazole analogs of 2-methoxyestradiol
Solum, Eirik Johansson,Vik, Anders,Hansen, Trond Vidar
, p. 46 - 53 (2014/07/07)
Thirteen 1,4-disubstituted 1,2,3-triazole analogs of 2-methoxyestradiol were prepared and tested for their cytotoxic and tubulin polymerization inhibition effects. Two compounds, 11j and 11k, exhibited anti-proliferative effects at low micromolar concentr
