ABSTRACT
Cancer cells preferentially use glycolysis rather than oxidative phosphorylation for their rapid growth. They consume large amount of glucose to produce lactate even when oxygen is abundant, a phenomenon known as the Warburg effect. This metabolic change originates from a shift in the expression of alternative spliced isoforms of the glycolytic enzyme pyruvate kinase (PK), from PKM1 to PKM2. While PKM1 is constitutively active, PKM2 is switched from an inactive dimer form to an active tetramer form by small molecule activators. The prevalence of PKM2 in cancer cells relative to the prevalence of PKM1 in many normal cells, suggests a therapeutic strategy whereby activation of PKM2 may counter the abnormal cellular metabolism in cancer cells, and consequently decreased cellular proliferation. Herein we describe the discovery and optimization of a series of PKM2 activators derived from the 2-((2,3-dihydrobenzo[b][1,4] dioxin-6-yl)thio)-1-(2-methyl-1-(methylsulfonyl)indolin-5-yl) ethanone scaffold. The synthesis, SAR analysis, enzyme active site docking, enzymatic reaction kinetics, selectivity and pharmaceutical properties are discussed.
Subject(s)
Carrier Proteins/agonists , Enzyme Activation/drug effects , Indoles/chemistry , Indoles/pharmacology , Membrane Proteins/agonists , Neoplasm Proteins/agonists , Neoplasms/enzymology , Thyroid Hormones/agonists , Caco-2 Cells , Carrier Proteins/metabolism , Humans , Membrane Proteins/metabolism , Molecular Docking Simulation , Neoplasm Proteins/metabolism , Neoplasms/drug therapy , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Protein Multimerization/drug effects , Pyruvate Kinase/metabolism , Sulfinic Acids/chemistry , Sulfinic Acids/pharmacology , Thyroid Hormones/metabolism , Thyroid Hormone-Binding ProteinsABSTRACT
Bidentate phosphine ligands have been prepared on polystyrene beads modified with polyether dendron spacers. When complexed to Pd(0), these systems exhibited a negative dendritic effect on Heck catalysis (contrary to the analogous monodentate phosphine systems), but mostly a positive influence on carbonylation. This opposite influence of the dendronization falls into line with other differences in the optimal ligand structure for the two reactions. The negative effect on the Heck catalysis with bidentate phosphines may indicate that dendrimer-induced reduction in the cross-linking upon Pd complexation is responsible for the positive effect in the corresponding monodentate phosphine systems.
ABSTRACT
The yield and enantioselectivity of an asymmetric aldol reaction, catalyzed by a proline derivative immobilized on polystyrene via dipolar cycloaddition, are remarkably improved by the dendronization of the support.
