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3 results on '"Szeremeta-Spisak J"'

1. Synthesis of amide and sulfonamide substituted N-aryl 6-aminoquinoxalines as PFKFB3 inhibitors with improved physicochemical properties.

Author

Boutard N, Białas A, Sabiniarz A, Guzik P, Banaszak K, Biela A, Bień M, Buda A, Bugaj B, Cieluch E, Cierpich A, Dudek Ł, Eggenweiler HM, Fogt J, Gaik M, Gondela A, Jakubiec K, Jurzak M, Kitlińska A, Kowalczyk P, Kujawa M, Kwiecińska K, Leś M, Lindemann R, Maciuszek M, Mikulski M, Niedziejko P, Obara A, Pawlik H, Rzymski T, Sieprawska-Lupa M, Sowińska M, Szeremeta-Spisak J, Stachowicz A, Tomczyk MM, Wiklik K, Włoszczak Ł, Ziemiańska S, Zarębski A, Brzózka K, Nowak M, and Fabritius CH

Subjects
HCT116 Cells, Humans, Kinetics, Solubility, Amides chemistry, Phosphofructokinase-2 antagonists & inhibitors, Quinoxalines chemistry, Quinoxalines pharmacology, Sulfonamides chemistry
Abstract

In oncology, the "Warburg effect" describes the elevated production of energy by glycolysis in cancer cells. The ubiquitous and hypoxia-induced 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) plays a noteworthy role in the regulation of glycolysis by producing fructose-2,6-biphosphate (F-2,6-BP), a potent activator of the glycolysis rate-limiting phosphofructokinase PFK-1. Series of amides and sulfonamides derivatives based on a N-aryl 6-aminoquinoxaline scaffold were synthesized and tested for their inhibition of PFKFB3 in vitro in a biochemical assay as well as in HCT116 cells. The carboxamide series displayed satisfactory kinetic solubility and metabolic stability, and within this class, potent lead compounds with low nanomolar activity have been identified with a suitable profile for further in vivo evaluation., (Copyright © 2018. Published by Elsevier Ltd.)

Published
2019
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2. Discovery and Structure-Activity Relationships of N-Aryl 6-Aminoquinoxalines as Potent PFKFB3 Kinase Inhibitors.

Author

Boutard N, Białas A, Sabiniarz A, Guzik P, Banaszak K, Biela A, Bień M, Buda A, Bugaj B, Cieluch E, Cierpich A, Dudek Ł, Eggenweiler HM, Fogt J, Gaik M, Gondela A, Jakubiec K, Jurzak M, Kitlińska A, Kowalczyk P, Kujawa M, Kwiecińska K, Leś M, Lindemann R, Maciuszek M, Mikulski M, Niedziejko P, Obara A, Pawlik H, Rzymski T, Sieprawska-Lupa M, Sowińska M, Szeremeta-Spisak J, Stachowicz A, Tomczyk MM, Wiklik K, Włoszczak Ł, Ziemiańska S, Zarębski A, Brzózka K, Nowak M, and Fabritius CH

Subjects
Cell Survival drug effects, Crystallography, X-Ray, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, HCT116 Cells, Humans, Lactic Acid antagonists & inhibitors, Lactic Acid biosynthesis, Models, Molecular, Molecular Structure, Phosphofructokinase-2 metabolism, Quinoxalines chemical synthesis, Structure-Activity Relationship, Drug Discovery, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Phosphofructokinase-2 antagonists & inhibitors, Quinoxalines chemistry, Quinoxalines pharmacology
Abstract

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 IC 50 of 14 nm for the target and an IC 50 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., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Published
2019
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3. 1-Sulfonyl-6-Piperazinyl-7-Azaindoles as potent and pseudo-selective 5-HT6 receptor antagonists.

Author

Fabritius CH, Pesonen U, Messinger J, Horvath R, Salo H, Gałęzowski M, Galek M, Stefańska K, Szeremeta-Spisak J, Olszak-Płachta M, Buda A, Adamczyk J, Król M, Prusis P, Sieprawska-Lupa M, Mikulski M, Kuokkanen K, Chapman H, Obuchowicz R, Korjamo T, Jalava N, and Nowak M

Subjects
Amnesia chemically induced, Animals, Behavior, Animal drug effects, Dose-Response Relationship, Drug, Humans, Indoles chemical synthesis, Indoles chemistry, Maze Learning drug effects, Mice, Models, Molecular, Molecular Structure, Piperazines chemical synthesis, Piperazines chemistry, Scopolamine, Serotonin Antagonists chemical synthesis, Serotonin Antagonists chemistry, Structure-Activity Relationship, Sulfones chemical synthesis, Sulfones chemistry, Amnesia drug therapy, Indoles pharmacology, Piperazines pharmacology, Receptors, Serotonin metabolism, Serotonin Antagonists pharmacology, Sulfones pharmacology
Abstract

A series of 1-Sulfonyl-6-Piperazinyl-7-Azaindoles, showing strong antagonistic activity to 5-HT6 receptor (5-HT6R) was synthesized and characterized. The series was optimized to reduce activity on D2 receptor. Based on the selectivity against this off-target and the analysis of the ADME-tox profile, compound 1c was selected for in vivo efficacy assessment, which demonstrated procognitive effects as shown in reversal of scopolamine induced amnesia in an elevated plus maze test in mice. Compound 3, the demethylated version of compound 1c, was profiled against a panel of 106 receptors, channels and transporters, indicating only D3 receptor as a major off-target. Compound 3 has been selected for this study over compound 1c because of the higher 5-HT6R/D2R binding ratio. These results have defined a new direction for the design of our pseudo-selective 5-HT6R antagonists., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Published
2016
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