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.
Subject(s)
Amides/chemistry , Phosphofructokinase-2/antagonists & inhibitors , Quinoxalines/chemistry , Quinoxalines/pharmacology , Sulfonamides/chemistry , HCT116 Cells , Humans , Kinetics , SolubilityABSTRACT
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-biphosphataseâ 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 14â nm for the target and an IC50 of 0.49â 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.
Subject(s)
Drug Discovery , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Phosphofructokinase-2/antagonists & inhibitors , Quinoxalines/chemistry , Quinoxalines/pharmacology , 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 RelationshipABSTRACT
The scope of ruthenium (Ru)-catalyzed cross metathesis (CM) of allyl-decorated polyhedral oligomeric silsesquioxanes (POSS) was explored. A variety of different commercial and non-commercial ruthenium complexes were tested to determine that the nitro-activated Ru catalyst is optimal for this transformation. The reported transformation was used to prepare selected hybrid steroid-POSS compounds.
Subject(s)
Organosilicon Compounds/chemistry , Organosilicon Compounds/chemical synthesis , Ruthenium/chemistry , CatalysisABSTRACT
Due to the changing needs of consumers and the increased risk of diet-related diseases, today's consumers are forced to seek alternative types of meat. It should, on one hand be tasty, and on the other will improve the health of the consumer. Game is considered to be such a meat. Although Poland is one of the leading producers and exporters of game in Europe, the level of its consumption is very low at about 0.08kg/person/year. Based on quantitative data from 1000 respondents a model predicting the consumption of wild game based on logistic regression has been prepared. It was demonstrated that consumers are likely to increase their consumption of game, provided that it will have a higher quality and greater commercial availability. A higher propensity to change eating habits in respect of game was displayed mainly by men, city dwellers and those who evaluated their own knowledge on nutritional and diet higher than others.
Subject(s)
Consumer Behavior , Food Preferences/psychology , Meat , Adult , Animals , Animals, Wild , Commerce , Female , Food Quality , Humans , Male , Middle Aged , Poland , Surveys and QuestionnairesABSTRACT
An aryl amine attached to the meso position of a porphyrin controls the π-delocalization using a redox process or a protonation/deprotonation centered at the meso-nitrogen. An easily accessible modulated motif affords a switchable near-IR chromophore as reflected by significant changes in absorption and fluorescence spectra.
