Inhibition of Quorum-Sensing Regulator from Pseudomonas aeruginosa Using a Flavone Derivative.

Quorum sensing (QS) is a cell-to-cell communication process that controls bacterial collective behaviors. The QS network regulates and coordinates bacterial virulence factor expression, antibiotic resistance and biofilm formation. Therefore, inhibition of the QS system is an effective strategy to suppress the bacterial virulence. Herein, we identify a phosphate ester derivative of chrysin as a potent QS inhibitor of the human pathogen Pseudomonas aeruginosa (P. aeruginosa) using a designed luciferase reporter assay. In vitro biochemical analysis shows that the chrysin derivative binds to the bacterial QS regulator LasR and abrogates its DNA-binding capability. In particular, the derivative exhibits higher anti-virulence activity compared to the parent molecule. All the results reveal the potential application of flavone derivative as an anti-virulence compound to combat the infectious diseases caused by P. aeruginosa.

Efficient Synthesis of Phosphonamidates through One-Pot Sequential Reactions of Phosphonites with Iodine and Amines.

A one-pot sequential strategy to construct phosphonamidates has been developed by generating phosphonites in situ from arylmagnesium bromides and triethyl phosphite followed by treatment with iodine and amines. A variety of phosphonamidates were obtained with good to excellent yields at room temperature from easily available materials.

Transcriptome analysis of three cultivars of Poria cocos reveals genes related to the biosynthesis of polysaccharides.

Poria cocos (P. cocos) polysaccharides (PCPs) are used to improve immunity and possess antitumor activities. We compared three cultivars of P. cocos (5.78, XJ 28 and JHYH) PCP contents. Then we determined that malZ, galA, SORD, gnl and bglX are key enzymes within the PCP biosynthetic pathway by using HiSeq2500 transcriptome and qRT-PCR validation. Our results provide more detailed information about the PCP biosynthesis pathway at the molecular level in P. cocos and establish the functions for the molecular breeding to produce polysaccharides in general for therapeutic use in Chinese medicinal plants.

Reinvestigation of the iodine-mediated phosphoramidation reaction of amines and P(OR)3 and its synthetic applications.

A systematic study on the iodine-mediated phosphoramidation reaction of amines and trialkyl phosphites was conducted, which not only disclosed the factors affecting the reaction but also revealed that it could proceed smoothly in CH2Cl2 at room temperature in open air. Using this method, various phosphoramidates with different aliphatic amines and aromatic amines were synthesized in good to excellent yields. Our present investigation shows that this underused method is actually a mild, practical and general way to synthesize phosphoramidates and will have wide applications.

Synthesis of phostones via DABCO-catalyzed bromocyclization of alkenylphosphonic acid monoesters.

The bromocyclization of 4-aryl-3-butenylphosphonic acid monoesters could proceed smoothly and rapidly in CH3CN with 1.2 equiv. of NBS in the presence of 0.02 equiv. of DABCO at room temperature, giving exclusively the six-membered ring bromophostones with high endo regioselectivity but poor diastereoselectivity. The diastereomers were separated and their relative configurations were determined based on their NMR analysis and X-ray crystallography. Furthermore, we preliminarily demonstrated that the asymmetric bromocyclization of these kinds of substrates was possible.

Synthesis of phosphaisocoumarin amidates via DIBAL-H-mediated selective amidation of phosphaisocoumarin esters.

A series of phosphaisocoumarin amidates were synthesized for the first time via DIBAL-H-mediated direct amidation of phosphaisocoumarin esters under mild conditions in good to excellent yields. The present reaction showed high selectivity. In each case, the phostone ring was intact and only the exocyclic ethoxy group was amidated. A plausible mechanism of the reaction was provided.

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.

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.

Phosphaisocoumarins as a new class of potent inhibitors for pancreatic cholesterol esterase.

Due to the importance of pancreatic cholesterol esterase (CEase) as a potential target in atherosclerosis and for the development of hypocholesterolemic agents, there are increasing interests in designing and synthesizing CEase inhibitors. In the present study, we prepared forty-five isocoumarin phosphorus analogues (i.e., phosphaisocoumarins) and investigated the inhibition of these compounds on the CEase. The results showed that some phosphaisocoumarins could act as potent inhibitors of CEase. The most potent inhibitors, compounds 9d, 10a and 12e give IC50 values of 4.8 microM, 2.3 microM and 1.9 microM, respectively. The inhibition mechanism and kinetic characterization studies indicate that they are reversible competitive inhibitors.

An efficient route to 4-halophosphaisocoumarins via CuX2-mediated direct halocyclization of 2-(1-alkynyl)phenylphosphonic acid diesters.

A series of 4-halophosphaisocoumarins were synthesized via CuX2 (X = Br, Cl) -mediated direct halocyclization of 2-(1-alkynyl)phenylphosphonic acid diesters in dichloroethane with the addition of n-Bu4NX or/and AgI in good to excellent yields. This reaction provides an efficient route to 4-halophosphaisocoumarins and represents the first example of bromo- and chlorocyclization of unsaturated phosphonic acid diesters.

Synthesis of 2H-1,2-oxaphosphorin 2-oxides via Ag2CO3-catalyzed cyclization of (Z)-2-alken-4-ynylphosphonic monoesters.

[reaction: see text]. Six new 2-ethoxy-2H-1,2-oxaphosphorin 2-oxides were synthesized with high regioselectivity in good yields via Ag(2)CO(3)-catalyzed cyclization of (Z)-2-alken-4-ynylphosphonic monoesters in CH(2)Cl(2) at room temperature. This cyclization of P-OH to substituted alkynes is reported for the first time. The products are a class of phosphorus heterocycles with potential use and are heretofore prepared with difficulty.

Synthesis of phosphaisocoumarins via iodocyclization.

4-Iodophosphaisocoumarins can be prepared in good yield and with high regioselectivity under mild conditions by the reaction of o-(1-alkynyl)phenylphosphonates with I(2) or ICl. The present reaction represents the first example of a phosphonate iodocyclization onto a C-C triple bond. The resulting iodides can be further elaborated using palladium-catalyzed coupling reactions.

The synthesis of phosphaisocoumarins by Cu(I)-catalyzed intramolecular cyclization of o-ethynylphenylphosphonic acid monoesters.

Cu(I)-catalyzed intramolecular cyclization of o-ethynylphenylphosphonic acid monoethyl esters was examined, and a new class of six-membered phosphorus heterocycles was formed with high regioselectivity and good yields. The present reaction is the first example of intramolecular addition of P-OH to alkynes, which provides a convenient way to synthesize novel phosphorus heterocycles having potential bioactivities.