1667-98-7Relevant academic research and scientific papers
New estrogen receptor antagonists. 3,20-Dihydroxy-19-norpregna-1,3,5(10)-trienes: Synthesis, molecular modeling, and biological evaluation
Kuznetsov, Yury V.,Levina, Inna S.,Scherbakov, Alexander M.,Andreeva, Olga E.,Fedyushkina, Irina V.,Dmitrenok, Andrey S.,Shashkov, Alexander S.,Zavarzin, Igor V.
, p. 670 - 682 (2017/12/08)
New estrogen receptor α (ERα) antagonists – 3,20-dihydroxy-19-norpregna-1,3,5(10)-trienes containing an additional carbocyclic ring D′ at the 16α,17α positions – were synthesized. The effects of the new compounds on the MCF-7 breast cancer cells and ERα activation were investigated. All the steroids studied were synthesized starting from estrone methyl ether. The scaffold of compounds containing the six-membered ring D′ was constructed via the Diels–Alder reaction of butadiene with 3-methoxy-19-norpregna-1,3,5(10),16-tetraen-20-one 5. The hydrogenation of primary 16α,17α-cyclohexeno-adduct 7 followed by 3-demethylation (by HBr–AcOH) and reduction of 20-oxo group (by LiAlH4) or in one step by DIBAH gave target mono- and dihydroxy steroids 9–11. The Corey–Chaykovsky reaction of the same 3-methoxy-19-norpregna-1,3,5(10),16-tetraen-20-one 5 gave 16α,17α-methylene-substituted compound. The reaction of the latter with DIBAH immediately yielded 3,20-dihydroxy-16α,17α-methyleno-19-norpregna-1,3,5(10)-triene 13. The same procedures using 3-methoxy-19-norpregna-1,3,5(10),16-tetraen-20-one 5 produced corresponding 3,20-dihydroxy-16,17-19-norpregna-1,3,5(10)-triene 16 and 3,20-dihydroxy-19-norpregna-1,3,5(10),16-tetraene 17. All compounds were fully characterized by 1D and 2D NMR, HRMS, and X-ray diffraction. The molecular docking showed that the target compounds can bind to ER, their binding mode being similar to that of natural estradiol. 16α,17α-Methylene- or unsubstituted compounds exhibit the highest cytotoxicity against MCF-7 cells, being simultaneously relatively weak ERα inhibitors. 3,20-Dihydroxy steroids containing the six-membered ring D′ proved to be the most effective ERα inhibitors. These compounds displayed moderate cytotoxicity comparable of that of tamoxifen and showed no toxic effect on MCF-10A normal, nontumorigenic epithelial cells. The new ER antagonists were found to be good candidates for further testing as agents for the treatment and prevention of ERα-positive breast cancers.
Estrone sulfamate inhibitors of estrone sulfatase, and associated pharmaceutical compositions and methods of use
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, (2008/06/13)
Novel compounds useful as inhibitors of estrone sulfatase are provided. The compounds have the structural formula (I) wherein r1 is an optional double bond, R1 and R2 are selected from the group consisting of hydrogen and lower alky, or together form a cy
Stereoelectronically Controlled, Thallium(III)-Mediated C-19 Degradation of 19-Hydroxy Steroids. An Expedient Route to Estrone and its Congeners via 19-Nor-10β-hydroxy Intermediates
Kocovsky, Pavel,Baines, Richard S.
, p. 5439 - 5444 (2007/10/02)
Estrone (8b) has been synthesized in four steps from 3β-acetoxy-19-hydroxyandrost-5-en-17-one (2b), readily available from an industrial precursor.A key feature of the strategy is a stereoelectronically controlled, Tl(III)-mediated degradation (2b -> 5b).Oppenauer oxidation of diol 6b, resulting from saponification of the acetate 5b, afforded the unsaturated 10β-hydroxy ketone 7b, acid treatment of which induced aromatization affording 8b.An alternative route including dehydration (5b -> 9b) followed by Oppenauer oxidation (10b -> 8b) gave comparable results.This strategy has first been developed with the aid of cholestane model compounds (2a -> 5a) and then successfully applied to the synthesis of analogues in the cholestane, androstane, and pregnane series to produce the corresponding 19-nor-10β-hydroxy derivatives 7a-d and A-aromatic steroids 8a-d.
