- Balanced dual acting compounds targeting aromatase and estrogen receptor α as an emerging therapeutic opportunity to counteract estrogen responsive breast cancer
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Breast Cancer (BC) is a leading cause of death in women, currently affecting 13% of female population worldwide. First-line clinical treatments against Estrogen Receptor positive (ER+) BC rely on suppressing estrogen production, by inhibiting the aromatase (AR) enzyme, or on blocking estrogen-dependent pro-oncogenic signaling, by targeting Estrogen Receptor (ER) α with selective Modulators/Degraders (SERMs/SERDs). The development of dual acting molecules targeting AR and ERα represents a tantalizing alternative strategy to fight ER + BC, reducing the incidence of adverse effects and resistance onset that limit the effectiveness of these gold-standard therapies. Here, in silico design, synthesis, biological evaluation and an atomic-level characterization of the binding and inhibition mechanism of twelve structurally related drug-candidates enable the discovery of multiple compounds active on both AR and ERα in the sub-μM range. The best drug-candidate 3a displayed a balanced low-nanomolar IC50 towards the two targets, SERM activity and moderate selectivity towards a BC cell line. Moreover, most of the studied compounds reduced ERα levels, suggesting a potential SERD activity. This study dissects the key structural traits needed to obtain optimal dual acting drug-candidates, showing that multitarget compounds may be a viable therapeutic option to counteract ER + BC.
- Belluti, Federica,Bisi, Alessandra,Caciolla, Jessica,Fimognari, Carmela,Gobbi, Silvia,Magistrato, Alessandra,Martini, Silvia,Pavlin, Matic,Rampa, Angela,Simonelli, Federica,Spinello, Angelo,Turrini, Eleonora,Zaffaroni, Nadia
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supporting information
(2021/08/09)
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- Iron-catalyzed domino decarboxylation-oxidation of α,β-unsaturated carboxylic acids enabled aldehyde C-H methylation
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A practical and general iron-catalyzed domino decarboxylation-oxidation of α,β-unsaturated carboxylic acids enabling aldehyde C-H methylation for the synthesis of methyl ketones has been developed. This mild, operationally simple method uses ambient air as the sole oxidant and tolerates sensitive functional groups for the late-stage functionalization of complex natural-product-derived and polyfunctionalized molecules.
- Gong, Pei-Xue,Xu, Fangning,Cheng, Lu,Gong, Xu,Zhang, Jie,Gu, Wei-Jin,Han, Wei
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supporting information
p. 5905 - 5908
(2021/06/18)
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- SUBSTITUTED BIARYLS, PROCESS FOR THEIR MANUFACTURE AND USE THEREOF AS MEDICAMENTS
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The present invention relates to compounds of general formula (I) wherein A, B, L, R1, R2, R3a and R3b are defined as in the specification, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, which have valuable properties.
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Page/Page column 48
(2010/11/30)
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- Synthesis of 4(5)-Acyl-, 1-Substituted 5-Acyl, and 1-Substituted 4-Acyl-1H-imidazoles from 4-Aminoisoxazoles
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4-Aminoisoxazoles can be acylated with a wide variety of activated carboxylic acids.Hydrogenation of the resulting amides gives α-(acylamino)enaminones, which cyclize to 4(5)-acylimidazoles upon treatment with base.This method allows for the synthesis of acylimidazoles with a wide range of substituents at C-2.Utilization of N-substituted 4-aminoisoxazoles in the same sequence of reactions yields 1-substituted 5-acylimidazoles, a substitution pattern not otherwise easily prepared.Treatment of α-(acylamino)enaminones, derived from N-unsubstituted isoxazoles, with primary amines leads to incorporation of the amine at the β-position with concomitant expulsion of ammonia.This sequence efficiently yields 1-substituted and 1,2-disubstituted 4-acylimidazoles but does not give satisfactory yields of 5-substituted 4-acylimidazoles due to steric inhibition of the amine exchange.
- Reiter, Lawrence A.
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p. 2714 - 2726
(2007/10/02)
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- A GENERAL SYNTHESIS OF 4(5)-ACYLIMIDAZOLES FROM 4-ACYLAMINOISOXAZOLES.
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2-Substituted-4(5)-acyl, 1,2-disubstituted 4-acyl and 1,2-disubstituted-5-acylimidazoles can be specifically prepared from 4-aminoisoxazoles.
- Reiter, Lawrence A.
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p. 3423 - 3426
(2007/10/02)
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- PYROLISE-ECLAIR EN PHASE GAZEUSE DU 1-ACETYLIMIDAZOLE.
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1-acetylimidazole is isomerized into 2- and 4-acetylimidazoles and under flash-vacuum pyrolytic conditions.This has been demonstrated by a real-time analysis of the products using mass and ion kinetic energy spectrometries.
- Maquestiau, A.,Tommasetti, A.,Pedregal-Freire, C.,Elguero, J.,Flammang, R.
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p. 1067 - 1072
(2007/10/02)
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- 2-GUANIDINO-4-HETEROARYL-THIAZOLES
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A series of 2-guanidino-4-heteroarylthiazoles, wherein the heteroaryl substituent is selected from thiazolyl, triazolyl, imidazolyl, and 2-alkyl, 2-amino and 2-carboxamido derivatives thereof, are disclosed. The novel compounds have activity as antisecretory agents and histamine H 2 antagonists and are useful for the treatment of gastric hyperacidity and peptic ulcers. Also disclosed are pharmaceutical compositions containing the novel compounds of this invention and a method of using the compounds in the treatment of gastric hyperacidity and peptic ulcers. Novel intermediates useful in the preparation of the novel antisecretory compounds are also described.
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