- Discovery and Structure–Activity Relationships of N-Aryl 6-Aminoquinoxalines as Potent PFKFB3 Kinase Inhibitors
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Energy and biomass production in cancer cells are largely supported by aerobic glycolysis in what is called the Warburg effect. The process is regulated by key enzymes, among which phosphofructokinase PFK-2 plays a significant role by producing fructose-2,6-biphosphate; the most potent activator of the glycolysis rate-limiting step performed by phosphofructokinase PFK-1. Herein, the synthesis, biological evaluation and structure–activity relationship of novel inhibitors of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), which is the ubiquitous and hypoxia-induced isoform of PFK-2, are reported. X-ray crystallography and docking were instrumental in the design and optimisation of a series of N-aryl 6-aminoquinoxalines. The most potent representative, N-(4-methanesulfonylpyridin-3-yl)-8-(3-methyl-1-benzothiophen-5-yl)quinoxalin-6-amine, displayed an IC50 of 14 nm for the target and an IC50 of 0.49 μm for fructose-2,6-biphosphate production in human colon carcinoma HCT116 cells. This work provides a new entry in the field of PFKFB3 inhibitors with potential for development in oncology.
- Boutard, Nicolas,Bia?as, Arkadiusz,Sabiniarz, Aleksandra,Guzik, Pawe?,Banaszak, Katarzyna,Biela, Artur,Bień, Marcin,Buda, Anna,Bugaj, Barbara,Cieluch, Ewelina,Cierpich, Anna,Dudek, ?ukasz,Eggenweiler, Hans-Michael,Fogt, Joanna,Gaik, Monika,Gondela, Andrzej,Jakubiec, Krzysztof,Jurzak, Mirek,Kitlińska, Agata,Kowalczyk, Piotr,Kujawa, Maciej,Kwiecińska, Katarzyna,Le?, Marcin,Lindemann, Ralph,Maciuszek, Monika,Mikulski, Maciej,Niedziejko, Paulina,Obara, Alicja,Pawlik, Henryk,Rzymski, Tomasz,Sieprawska-Lupa, Magdalena,Sowińska, Marta,Szeremeta-Spisak, Joanna,Stachowicz, Agata,Tomczyk, Mateusz M.,Wiklik, Katarzyna,W?oszczak, ?ukasz,Ziemiańska, Sylwia,Zar?bski, Adrian,Brzózka, Krzysztof,Nowak, Mateusz,Fabritius, Charles-Henry
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- Rh(iii)-Catalyzed regioselective C4 alkylation of indoles with allylic alcohols: Direct access to β-indolyl ketones
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A Rh(iii)-catalyzed and weak coordination carbonyl guided direct C4 alkylation of indoles with allylic alcohols was developed with excellent regioselectivity. This reaction was conducted under mild conditions, leading to a variety of β-indolyl ketones with good functional group tolerance in moderate to good yields.
- Pan, Changduo,Huang, Gao,Shan, Yujia,Li, Yiting,Yu, Jin-Tao
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supporting information
p. 3038 - 3042
(2020/05/08)
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- SUBSTITUTED QUINOXALINE DERIVATIVES
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The present invention relates to substituted quinoxaline derivatives. These compounds are useful for the prevention and/or treatment of several medical conditions including hyperproliferative disorders and diseases.
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Page/Page column 160; 161
(2016/11/28)
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- SUBSTITUTED QUINOXALINE DERIVATIVES
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The present invention relates to substituted quinoxaline derivatives. These compounds are useful for the prevention and/or treatment of several medical conditions including hyperproliferative disorders and diseases.
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Page/Page column 255
(2016/12/01)
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- GLUCOSYLCERAMIDE SYNTHASE INHIBITORS FOR THE TREATMENT OF DISEASES
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Described herein are compounds of Formula I, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or conditions associated with the enzyme glucosylceramide synthase (GCS).
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Paragraph 0001190
(2015/04/15)
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- Heterocyclic compounds for the treatment of migraine
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Described herein are compounds useful in the treatment of migraine, which have the general formula: wherein: W is a CH group or a N atom; Z is N or C—R4; B and D are selected independently from CH and N, with the proviso that at least one of B and D is CH and with the further proviso that one of B and D can represent N only when W and Z are both other than N; A is a group of Formula II, III or IV, such that group A contains at least 1 N atom; NR7 is either —NH— or —N═;is a single or double bond; X is a N atom, a CH group or a C(OH) group whenis a single bond; or, whenis a double bond, a C atom; Y is an NH, N-alkyl, N-benzyl or CH2group; U and V each represent a N atom or a CH group, with the proviso that both cannot be N; a and b are, independently, 0 or 1; c is an integer from 0 to 3; d is an integer from 1 to 3; e is an integer from 1 to 2; f is an integer from 0 to 3; g is an integer from 3 to 6 and h is an integer from 2 to 3; such that the sum of c and d is at least 2 and the sum of e and f is at least 2; and salts and solvates thereof.
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Page column 33
(2010/11/30)
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