Inhibitory and Activating Effects of Some Flavonoid Derivatives on Human Pyruvate Kinase Isoenzyme M2

Abstract

Pyruvate kinase isoenzyme M2 (PKM2) is expressed excessively in many different cancer types and it plays an important role in the control of glucose metabolism. Thus, it is evaluated as an important target in the development of medication for cancer. The flavonoids comprise a large group of natural products with variable phenolic structures and occur mainly in plants. They are of great interest due to their biological properties. In this study, the effects of various flavonoid derivatives on the PKM2 enzyme activity were analyzed in vitro. The flavonoid derivatives 1 and 2 showed inhibition effect with IC50 values of <60 μM. IC50 values of compounds 3-8 were calculated as 134, 415, 145, 163, 295 μM, and 3.5 mM, respectively. The molecules 9-12 showed an activation effect with values of AC50 of less than 90 μM. The IC50 values of the derivatives 13-17 were calculated as 115, 150, 200, 221, and 275 μM, respectively. The results show that catechin derivatives can be probably used as lead compounds for the design of PKM2 enzyme activators and inhibitors.

Natural products targeting glycolytic signaling pathways-an updated review on anti-cancer therapy

“…In a separate study, researchers examined the in vitro effects of 22 flavonoid derivatives on PKM2 enzyme activity. Results indicated that catechin derivatives may be employed as lead molecules in the design of PKM2 enzyme activators and inhibitors (Adem et al, 2016). Isovitexin (Apigenin-6-Cglucoside, IVT) inhibited the proliferation and glucose Frontiers in Pharmacology frontiersin.org metabolism of A549 and H1975 cells by down-regulating the expression of PKM2 and its downstream factors (such as STAT3, Bcl-2, and Bcl-xl).…”

Ellagic Acid and Its Metabolites as Potent and Selective Allosteric Inhibitors of Liver Pyruvate Kinase

“…PKL inhibitors may be useful in halting NAFLD progression [ 7 ], but potent and selective inhibitors have not been reported in the literature. However, it is well known that some natural molecules, in particular polyphenolic compounds, potently inhibit the PKM2 isoform [ 15 , 16 , 17 ]. Most of these polyphenols have been found to possess a variety of pharmacological effects on oxidative stress, lipid metabolism, insulin resistance, and inflammation, which are all important pathological processes in the etiology of liver diseases such as NAFLD [ 18 , 19 , 20 , 21 ].…”

Synthesis and Antiproliferative Activity of Thioxoflavones Mannich Base Derivatives

“…Flavones are a group of natural products present in a wide variety of plants. They have been reported to possess a wide range of biological activities, including anticancer, antiviral, anti‐inflammatory, antioxidant, and cardiovascular actions .…”