Synthetic Flavonoids as Novel Modulators of Platelet Function and Thrombosis

Abstract

Cardiovascular diseases represent a major cause of mortality and morbidity in the world, and specifically, thrombotic conditions such as heart attacks and strokes are caused by unwarranted activation of platelets and subsequent formation of blood clots (thrombi) within the blood vessels during pathological circumstances. Therefore, platelets act as a primary therapeutic target to treat and prevent thrombotic conditions. Current treatments are limited due to intolerance, and they are associated with severe side effects such as bleeding complications. Hence, the development of novel therapeutic strategies for thrombotic diseases is an urgent priority. Flavonoids are naturally occurring plant-derived molecules that exert numerous beneficial effects in humans through modulating the functions of distinct cell types. However, naturally occurring flavonoids suffer from several issues such as poor solubility, lipophilicity, and bioavailability, which hinder their efficacy and potency. Despite these, flavonoids act as versatile templates for the design and synthesis of novel molecules for various therapeutic targets. Indeed, several synthetic flavonoids have recently been developed to improve their stability, bioavailability, and efficacy, including for the modulation of platelet function. Here, we provide insight into the actions of certain natural flavonoids along with the advantages of synthetic flavonoids in the modulation of platelet function, haemostasis, and thrombosis.

Untargeted Plasma Metabolomics and Gut Microbiome Profiling Provide Novel Insights into the Regulation of Platelet Reactivity in Healthy Individuals

“…Polyphenols can be found in a wide range of products, including fruits, vegetables, spices and herbs, dark chocolate, coffee, tea, and wine (reviewed in Manach et al 20 ). Our study validates previous reports that these polyphenols exert plateletinhibiting effects, 8 thereby strengthening the notion that diet influences platelet reactivity. However, there were no significant correlations between items from a food frequency questionnaire (for example, frequency of fruit, vegetables, alcohol, or caffeine consumption) and platelet reactivity (►Supplementary Fig.…”

“…exert platelet-inhibiting effects, 8 thereby strengthening the notion that diet influences platelet reactivity. However, there were no significant correlations between items from a food frequency questionnaire (for example frequency of fruit, vegetables, alcohol, or caffeine consumption) and platelet reactivity (Supplementary figure 4).…”

“…Over the years, different metabolites and metabolic pathways have been identified to influence platelet function and interact with platelet receptors. [7][8][9] A comprehensive overview of the association of plasma metabolites with platelet reactivity is however missing.…”

Src-family Protein Tyrosine Kinases: A promising target for treating Cardiovascular Diseases

“…Next, Vallance et al briefly analyzed the current knowledge on the impact of the flavonoids on the modulation of the platelet function, naturally occurring flavonoids such as nobiletin, tangeretin, quercetin, apigenin, luteolin, rhoifolin as well as synthetic flavonoids which had improved bioavailability including multiple synthetic 2,3-diphenyl-4H-pyrido(1,2-α)pyrimidin-4-one flavonoids, F-1 both could inhibit platelet activation via multiple mechanisms. However, at present, there is a lack of standardized use of flavonoids in clinical treatment guidelines 88 . The problems relating to the bioavailability, stability and multiple cellular targets of compounds remain to be solved.…”

Immobilized Crosslinked Pectinase Preparation on Porous ZSM-5 Zeolites as Reusable Biocatalysts for Ultra-Efficient Hydrolysis of β-Glycosidic Bonds

“…Therefore, the hydrolysis of flavonoid glucosides to produce high-value flavonoid aglycones is an important engineering application. Pectinase preparation can also hydrolyze the β-glycosidic bonds of flavonoid glycosides and transform flavonoid glycosides into the corresponding aglycones while avoiding the oxidation of flavonoid molecules ( Vallance et al, 2019 ; Cao et al, 2020 ).…”