- Halogen-substituted anthranilic acid derivatives provide a novel chemical platform for androgen receptor antagonists
-
Androgen receptor (AR) antagonists are used for hormone therapy of prostate cancer (PCa). However resistance to the treatment occurs eventually. One possible reason is the occurrence of AR mutations that prevent inhibition of AR-mediated transactivation by antagonists. To offer in future more options to inhibit AR signaling, novel chemical lead structures for new AR antagonists would be beneficial. Here we analyzed structure-activity relationships of a battery of 36 non-steroidal structural variants of methyl anthranilate including 23 synthesized compounds. We identified structural requirements that lead to more potent AR antagonists. Specific compounds inhibit the transactivation of wild-type AR as well as AR mutants that render treatment resistance to hydroxyflutamide, bicalutamide and the second-generation AR antagonist enzalutamide. This suggests a distinct mode of inhibiting the AR compared to the clinically used compounds. Competition assays suggest binding of these compounds to the AR ligand binding domain and inhibit PCa cell proliferation. Moreover, active compounds induce cellular senescence despite inhibition of AR-mediated transactivation indicating a transactivation-independent AR-pathway. In line with this, fluorescence resonance after photobleaching (FRAP) - assays reveal higher mobility of the AR in the cell nuclei. Mechanistically, fluorescence resonance energy transfer (FRET) - assays indicate that the amino-carboxy (N/C)-interaction of the AR is not affected, which is in contrast to known AR-antagonists. This suggests a mechanistically novel mode of AR-antagonism. Together, these findings indicate the identification of a novel chemical platform as a new lead structure that extends the diversity of known AR antagonists and possesses a distinct mode of antagonizing AR-function.
- Roell, Daniela,R?sler, Thomas W.,Hessenkemper, Wiebke,Kraft, Florian,Hauschild, Monique,Bartsch, Sophie,Abraham, Tsion E.,Houtsmuller, Adriaan B.,Matusch, Rudolf,van Royen, Martin E.,Baniahmad, Aria
-
-
- Synthesis and anti-parasitic activity of a novel quinolinone-chalcone series
-
A series of novel quinolinone-chalcone hybrids and analogues were designed, synthesized and their biological activity against the mammalian stages of Trypanosoma brucei and Leishmania infantum evaluated. Promising molecular scaffolds with significant microbicidal activity and low cytotoxicity were identified. Quinolinone-chalcone 10 exhibited anti-parasitic properties against both organisms, being the most potent anti-L. infantum agent of the entire series (IC50 value of 1.3 ± 0.1 μM). Compounds 4 and 11 showed potency toward the intracellular, amastigote stage of L. infantum (IC50 values of 2.1 ± 0.6 and 3.1 ± 1.05 μM, respectively). Promising trypanocidal compounds include 5 and 10 (IC 50 values of 2.6 ± 0.1 and 3.3 ± 0.1 μM, respectively) as well as 6 and 9 (both having IC50 values of 5 μM). Chemical modifications on the quinolinone-chalcone scaffold were performed on selected compounds in order to investigate the influence of these structural features on antiparasitic activity.
- Roussaki, Marina,Hall, Belinda,Lima, Sofia Costa,Da Silva, Anabela Cordeiro,Wilkinson, Shane,Detsi, Anastasia
-
supporting information
p. 6436 - 6441
(2013/11/19)
-
- Synthesis of mono-N-substituted functionalized anilines
-
The present invention relates to a process for direct and selective synthesis of mono-N-substituted functionalized anilines by using alkylating agents selected from the class of organic carbonates, preferably of the dialkyl, dibenzyl and diallyl types, in the presence of suitable catalysts that are chemically related to the class of aluminosilicates.
- -
-
-
- Synthesis of mono-N-substituted functionalized anilines
-
The present invention relates to a process for direct and selective synthesis of mono-N-substituted functionalized anilines by using alkylating agents selected from the class of organic carbonates, preferably of the dialkyl, dibenzyl and diallyl types, in the presence of suitable catalysts that are chemically related to the class of aluminosilicates.
- -
-
-
- Reaction of functionalized anilines with dimethyl carbonate over NaY faujasite. 3. Chemoselectivity toward mono-N-methylation
-
In the presence of NaY faujasite, dimethyl carbonate (MeOCO2Me, DMC) is a highly chemoselective methylating agent of functionalized anilines such as aminophenols (1), aminobenzyl alcohols (2), aminobenzoic acids (3), and aminobenzamides (4). The reaction proceeds with the exclusive formation of N-methylanilines without any concurrent O-methylation or N-/O-methoxy carbonylation side processes. Particularly, only mono-N-methyl derivatives [XC6H4NHMe, X = o-, m-, and p-OH; o- and p-CH 2OH; o- and P-CO2H; o- and p-CONH2] are obtained with selectivity up to 99% and isolated yields of 74-99%. DMC, which usually promotes methylations only at T > 120 °C, is activated by the zeolite catalyst and it reacts with compounds 1, 2, and 4, at 90 °C. Aminobenzoic acids (3) require a higher reaction temperature (≥130 °C).
- Selva, Maurizio,Tundo, Pietro,Perosa, Alvise
-
p. 7374 - 7378
(2007/10/03)
-
- Optimisation of aryl substitution leading to potent methionyl tRNA synthetase inhibitors with excellent Gram-positive antibacterial activity
-
Optimisation of the left-hand-side aryl moiety of a file compound screening hit against Staphylococcus aureus methionyl tRNA synthetase led to the identification of a series of potent nanomolar inhibitors. The best compounds showed excellent antibacterial activity against staphylococcal and enterococcal pathogens, including strains resistant to clinical antibiotics.
- Jarvest, Richard L.,Berge, John M.,Brown, Murray J.,Brown, Pamela,Elder, John S.,Forrest, Andrew K.,Houge-Frydrych,O'Hanlon, Peter J.,McNair, David J.,Rittenhouse, Stephen,Sheppard, Robert J.
-
p. 665 - 668
(2007/10/03)
-
- Decomposition of 2-dialkylaminobenzoyl azides to yield isocyanates and 1,1 -dialky lindazol-1-ium-3-olates
-
Substituted benzoyl azides normally yield the correspondingly substituted isocyanates but when a dialkylated amino group is in the 2-position, in addition to the isocyanate, the 1,1-dialkylated indazol-1-ium-3-olate is produced. The ratio of the two products is very variable depending upon the substitution in the benzene ring. Largest yields of the zwitterionic products were found when there was a substituent in the 3-position regardless of whether the substituent was electron-donating or -withdrawing.
- Waldron, Norman M.,Raza, Muhammad
-
p. 271 - 276
(2007/10/03)
-
- Reactions of Anthranilium Salts with Nucleophiles: Adduct Formation and Rearrangement
-
3-Unsubstituted anthranilium salts 1 react with alcohols in the presence of bases to yield adducts 5 which rearrange to the esters 4 when refluxed in xylene.Similar processes involving 1 and cyanide or azide also have been observed.Evidence favoring benzoazetinones 2 as rearrangement intermediates is presented.The chemistry of 1 with phosphines and phosphites is also described.For example, treatment of 1c with trimethyl phosphite yields the rearranged adduct salt 14 which cleaves to the acyl phosphonate 15 when treated with triethylamine.
- Vander Meer, Robert K.,Olofson, R. A.
-
p. 3373 - 3377
(2007/10/02)
-
- Synthesis, Stability, Structure, Reactivity, and Chemistry of N-Alkylbenzoazetinones
-
On treatment with triethylamine, 3-unsubstituted anthranilium salts 1 ring open and then recyclize to N-alkylbenzoazetinones 3.When the alkyl group is tertiary, 3 is stable and the X-ray crystal structure of one such derivative, N-1'-adamantylbenzoazetino
- Olofson, R. A.,Vander Meer, Robert K.,Hoskin, Dennis H.,Bernheim, Marguerite,Stournas, Stamoulis,Morrison, David S.
-
p. 3367 - 3372
(2007/10/02)
-