- 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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supporting information
p. 169 - 181
(2018/12/13)
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- 2-AMINO-BENZIMIDAZOLE DERIVATIVES AND THEIR USE AS 5-LIPOXYGENASE AND/OR PROSTAGLANDIN E SYNTHASE INHIBITORS
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The present invention relates to benzimidazole derivatives having the general formula I, wherein n is 0 or 1; X1 and X2 are independently, at each occurrence, CR5 or N; Y is C1-C6 alkylene, wherein alkylene is optionally substituted with one to two C1-C3 alkyl groups; R1 is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, -NH2, -NHR6, -NR7R8 and -NH-(R9)n-R10, n being 0 or 1; R2 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, -NH2, -NHR6, - NR7R8 and -NH-(R9)n-R10; R3 is selected from the group consisting of hydrogen, hydroxyl, OR11, -NR7R8, C1-C6 alkoxy, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C3 haloalkyl, -C(O)NHR11, aryl, heteroaryl and heterocyclyl, wherein each of said cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally and independently substituted with one to four Ra groups; and R4 is selected from the group consisting of -NH2, -N(R12)(V)pR13, - NH(V)p-OR14, -NHC(O)R15, and groups of formula la shown below, and their use in the treatment of diseases, in particular inflammatory diseases, cancer, stroke and/or Alzheimer's disease.
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Page/Page column 59
(2016/03/12)
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- Reaction of 2-Mercapto-4-chloro-6-bromobenzimidazole with Chloroacetic acid, &α-Halogenoketones and Alkyl Bromides
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The syntheses of 6-bromo-8-chlorothiazolobenzimidazol-3(2H)-one (4), 3-aryl-6-bromo-8-chlorothiazolobenzimidazoles (6), 2,3-dihydro-6-bromo-8-chloro-thiazolobenzimidazole (7) and 4H-2,3-dihydro-7-bromo-9-chlorothiazinobenz
- Jain, Kiran,Jain, K. K.,Chadha, V. K.,Handa, R. N.
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p. 1053 - 1056
(2007/10/02)
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