A new synthesis of fully phosphorylated flavones as potent pancreatic cholesterol esterase inhibitors.

Five flavones possessing one to four phenolic groups were fully phosphorylated efficiently and the obtained compounds showed excellent pancreatic cholesterol esterase (CEase) inhibitory activities with IC(50) in the nanomolar range, which were much more potent than their parent compounds. The inhibition mechanism and kinetic characterization studies indicate that they are irreversible competitive inhibitors.

Synthesis and biological evaluation of phosphorylated flavonoids as potent and selective inhibitors of cholesterol esterase.

A series of phosphorylated flavonoids were synthesized and investigated in vitro as inhibitors of pancreatic cholesterol esterase (CEase) and acetylcholinesterase (AChE). The results showed that most of the synthesized compounds exhibited nanomolar potency against CEase, much better than the parent flavonoids. Furthermore, these phosphorylated flavonoids demonstrated good to high selectivity for CEase over AChE, which only showed micromolar potency inhibition of AChE. The most selective and potent inhibitor of CEase (3e) had IC50 value of 0.72 nM and 11800-fold selectivity for CEase over AChE. The structure-activity relationships revealed that the free hydroxyl group at position 5 and phosphate group at position 7 of the phosphorylated flavonoids are favorable to the inhibition of CEase. The inhibition mechanism and kinetic characterization studies indicated that they are irreversible competitive inhibitors of CEase.

Inhibition of porcine liver carboxylesterase by phosphorylated flavonoids.

We have recently synthesized a series of phosphorylated flavonoids and identified some of them as potent inhibitors of pancreatic cholesterol esterase (CEase) with excellent selectivity for CEase over acetylcholinesterase (AChE). In the present paper, we investigated the inhibitory activities of these compounds against porcine liver carboxylesterase (CE) since carboxylesterases (CEs) are another family of serine esterases responsible for the metabolism and detoxification of many ester-containing xenobiotics and clinical esterified drugs, and there exists much structural similarity between CEase and CEs. The results indicated that phosphorylated flavonoids exhibited significantly improved inhibition potency toward CE than their parent compounds, and six of them had IC50 values less than 5.0nM. Among all compounds tested, compounds 3d and 3e are the two most potent inhibitors of CE, giving IC50 values of 1.79nM and 1.58nM, respectively. Interestingly, these compounds inhibited CEase and CE with similar structure activity correlations, and those with high inhibitory activities toward CEase could also inhibit CE efficiently. The presences of a free hydroxyl group at position 5 and a phosphate group at position 7 of the phosphorylated flavonoids are favorable to the inhibition of CE. The inhibition mechanism and kinetic characterization studies of the most potent inhibitors revealed that they are irreversible competitive inhibitors.