1667-98-7Relevant articles and documents
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Bowers et al.
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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.
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.
