Puerarin Derivatives Research Articles

Lipase-catalyzed synthesis of laurate esters from puerarin and its β-D-fructofuranosyl-(2→6)-puerarin derivative

This study investigates the transesterification of isoflavones puerarin and β-D-fructofuranosyl-(2→6)-puerarin to enhance their lipophilicity for specific pharmacological applications. The process achieved high yields (80-100%) in the isoflavones conversion when commercial lipases from Candida antarctica (CALB) and Thermomyces lanuginosus (TL IM) were used. The acylation patterns between CALB and TL IM varied depending on the substrate; both enzymes yielded principally monoacylated products from puerarin and β-D-fructofuranosyl-(2→6)-puerarin. However, TL IM also produced di- and triacylated derivatives of β-D-fructofuranosyl-(2→6)-puerarin in substantial amounts. Structural characterization by NMR identified puerarin-6ʹʹ-O-laurate and β-D-fructofuranosyl-(2→6)-puerarin-6ʹʹʹ-O-laurate as the primary products in CALB and TL IM reactions. These acyl derivatives presented improved lipophilicity (Log P from −1.0 − 0.16 to 3.26 − 3.58) and antioxidant activity (67.2-97.3 to 102.5-131.4 µM TE/mmol). Therefore, these compounds have potential pharmacological applications.

Green acetyl modification of puerarin to form puerarin 6′′-O-acetate using engineered Escherichia coli with favorable pathways and elevated acetyl-CoA supply

Green acetylation of puerarin to form puerarin 6′′-O-acetate using engineered Escherichia coli capable of synthesizing acetyl-CoA.

Glycosylation and methylation in the biosynthesis of isoflavonoids in Pueraria lobata.

The pathway for forming isoflavonoid skeletal structure is primarily restricted to the Leguminosae family. Subsequent decorations on the compound backbone by tailoring enzymes would change their biological and medicinal properties. Pueraria lobata is a leguminous plant, and as a traditional Chinese medicine its roots have been ascribed a number of pharmacological activities. Glycosylation and methylation are the main modifying processes in isoflavonoid metabolism in P. lobata roots, resulting in the accumulation of unique glycosylated and methylated end isoflavonoid compounds. For instance, daidzein 8-C-glucoside (i.e., puerarin) and puerarin derivatives are produced only by the Pueraria genus. Puerarin has been established as a clinical drug for curing cardiovascular diseases. To better understand the characteristic isoflavonoid metabolism in P. lobata, this review attempts to summarize the research progress made with understanding the main glycosylation and methylation of isoflavonoids in P. lobata and their biosynthetic enzymes.

Effects of Puerarin on the Prevention and Treatment of Cardiovascular Diseases.

Puerarin, an isoflavone glycoside derived from Pueraria lobata (Willd.) Ohwi, has been identified as a pharmacologically active component with diverse benefits. A large number of experimental and clinical studies have demonstrated that puerarin is widely used in the treatment of a variety of diseases. Among them, cardiovascular diseases (CVDs) are the leading cause of death in the world, and therefore remain one of the most prominent global public health concerns. In this review, we systematically analyze the preclinical investigations of puerarin in CVDs, such as atherosclerosis, cardiac hypertrophy, heart failure, diabetic cardiovascular complications, myocardial infarction, stroke and hypertension. In addition, the potential molecular targets of puerarin are also discussed. Furthermore, we summarize the clinical trails of puerarin in the treatment of CVDs. Finally, the therapeutic effects of puerarin derivatives and its drug delivery systems are overviewed.

Recent Advances in Methods of Puerarin Biotransformation.

Puerarin is an isoflavonoid extracted from the roots of Pueraria lobata in the Pueraria thomsonii family. Puerarin displays a broad range of pharmacological activities and has been widely used in clinics. However, puerarin's low solubility and permeability result in poor gastrointestinal absorption and low bioavailability. Simply increasing the dose does not effectively increase bioavailability and might lead to toxicity and side effects. Considerable progress has been achieved in the recent years on puerarin structural biotransformation using microorganisms and free enzymes. Increasingly numerous new puerarin derivatives with high solubility and bioactivity have been developed. This paper reviews recent progress in the biotransformation of puerarin.

STUDY ON THE SYNTHESIS OF PUERARIN DERIVATIVES AND THEIR ANTI-VASCULAR DEMENTIA ACTIVITY

<p class="lead">In this study, puerarin derivatives were designed by adding an active acetonitrile group that inhibits cyclooxygenase-2 (COX-2) in order to enhance the anti-vascular dementia drug activity. The acetonitrile group was linked to puerarin at the 7/4 'positions by a phenolic hydroxyl to give 7-mono-and 7, 4' di-substituted derivatives of puerarin. These structures were confirmed by <sup>1</sup>H NMR spectroscopy and MS spectroscopy. We compared the affinity of puerarin derivatives and puerarin for cyclooxygenase-2 (COX-2) using molecular docking. In addition, the anti-vascular dementia activity of the developed puerarin derivatives was studied by water maze, novel object recognition, and the determination of inducible nitric oxide synthase (iNOS) enzyme activity at the cerebral cortex of mice. Experimental results showed that the puerarin derivatives have a good affinity for COX-2 with therapeutic effects against vascular dementia. The results of this study suggest that the protective effects of the puerarin derivatives against vascular dementia may be related to suppression of inflammation associated with ischemia-reperfusion injury through inhibition of COX-2.</p>

Anticerebral Ischemia-Reperfusion Injury Activity of Synthesized Puerarin Derivatives.

When cerebral ischemia-reperfusion injury happened in patients, multiple pathological processes occur, such as leukocyte infiltration, platelet, and complement activation, which would result in cognitive dysfunction and inflammation. Puerarin has shown protective effect on injury of neural cell. In order to enhance this protective effect of puerarin, puerarin derivatives with different log⁡P values were designed and synthesized. The original phenolic hydroxyl in the puerarin molecules was substituted in order to change the blood-brain barrier permeability and thus enhance the efficacy for preventing cerebral ischemia/reperfusion injury. And the structure of the newly synthesized molecules was confirmed by 1H NMR spectroscopy and mass spectrometry. The mouse model of cerebral artery ischemia/reperfusion injury was established to test the anticerebral ischemia-reperfusion injury activity of the puerarin derivatives. The assays of the water maze, Y maze, brain cortex Ca2+-Mg2+-ATP enzyme, and iNOS enzyme activity were performed in this mouse model. The results showed that puerarin derivative P1-EA and P2-EA were resulting in an increased lipophilicity that enabled the derivatives to pass more efficiently through the blood-brain barrier, thus, improving the protective effects against cerebral ischemia/reperfusion injury. Therefore, derivatives of puerarin may serve as promising approach to improve neuron function in ischemia-reperfusion brain injury-related disorders.

Effects of Puerarin Derivative P on Learning, Memory and MPO Activity in Vascular Dementia Model Mice

Pharmacological experiments confirmed that Puerarin could not only expand the arterial vessels, increase the local blood flow, but also could protect the myocardium, improve the blood supply of ischemic tissue, which was used to treat the cerebrovascular dementia disease in clinical practice. Its own structure particularity caused the lower bioavailability and poorer solubility. In order to improve the deficiency, the related pharmacological experiments of the newly synthesized puerarin derivative (P), so as to expect the better curative effect than puerarin in the process of treating vascular dementia. The vascular dementia model was established by permanently ligating the common carotid artery in mice. The effects of puerarin derivative (P) on learning and memory in mice by water maze, Y maze and new object discrimination methods; The myeloperoxidase activity in the ischemic cerebral cortex was evaluated in mice by biochemical method. The experimental results showed that the mice spontaneous alternation response accuracy in Y maze could be obviously improved in 100mg/kg puerarin derivative group; In water maze, the swimming time to the safe platform would be significantly decreased in puerarin derivative group. Meanwhile, the MPO activity in the cerebral cortex of dementia mice was significantly decreased in 100mg/kg puerarin derivative group by permanently ligating the unilateral common carotid artery.

LC-MS/MS method for the determination of a new puerarin derivative and its application in pharmacokinetic studies in rats

LC-MS/MS method for the determination of a new puerarin derivative and its application in pharmacokinetic studies in rats

LC-MS/MS method for the determination of a new puerarin derivative and its application in pharmacokinetic studies in rats

AimTo establish a sensitive and rapid liquid chromatographic–tandem mass spectrometry (LC-MS/MS) method for the quantitative analysis of dehydrated puerarin in rat plasma, and its application for pharmacokinetic studies. MethodsA plasma sample was pretreated by one-step protein precipitation by the addition of five volumes of methanol. The chromatographic separation was achieved on a Zorbax SB-C18 column (4.6 mm × 150 mm I.D. 5.0 μm, Agilent, USA) at 40 °C at a flow rate of 0.6 mL·min−1 by an isocratic elution consisting of 10 mmol·L−1 ammonium acetate in methanol and water containing 0.1% formic acid in a ratio of 20 : 80 (V/V). Detection was performed on a triple quadrupole mass spectrometer in multiple-reaction monitoring (MRM) mode. An atmospheric pressure chemical ionization (APCI) interface in positive ionization mode was used by monitoring the transitions from m/z 399.1→281.0 (dehydrated puerarin) and m/z 271.0→215.0 (internal standard, IS). ResultsCalibration curves were linear in the concentration range from 1.50 to 5400 ng·mL−1, and the lower limit of quantification (LLOQ) was 1.50 ng·mL−1 in rat plasma. The accuracy and precision values, which were calculated from three different sets of quality control samples analyzed in sextuplicate on three different days, ranged from 95.73% to 103.18%, and from 4.33% to 7.86%, respectively. ConclusionThe method was successfully applied to assess the pharmacokinetics of dehydrated puerarin after oral administration in rats.

Phenol Acidity and Ease of Oxidation in Isoflavonoid/β-Carotene Antioxidant Synergism

Regeneration of β-carotene from the β-carotene radical cation by the 4'-propylpuerarin anion (second-order rate constant=1.5×10(9) L mol(-1) s(-1) in methanol/chloroform=1:9 (v/v) solution at 25 °C as determined by laser flash photolysis) was found to be marginally slower than regeneration by the 7-propylpuerarin anion (2.3×10(9) L mol(-1) s(-1)), in agreement with the 7-propylpuerarin anion being more reducing (E'=0.56 V vs NHE) than the 4'-propylpuerarin anion (E'=1.01 V vs NHE). The potentials were calculated from E°=1.12 and 1.44 V (vs NHE) as determined by cyclic voltametry in aqueous solution and pKa=9.51 and 7.23 obtained previously for 7-propylpuerarin and 4'-propylpuerarin, respectively. The less reducing but more acidic 4'-propylpuerarin showed less antioxidant activity in liposome of pH 7.4, but more significant antioxidant synergism with β-carotene than the more reducing but less acidic 7-propylpuerarin for oxidation initiated in the liposome lipid phase. Electrostatic effects are concluded to be important in the regeneration of β-carotene from the radical cation in the water/lipid interface because approximately 50% of 4'-propylpuerarin is present as the anion, whereas only 0.5% of 7-propylpuerarin is present as the anion. In contrast, penetration of the undissociated phenolic group into the lipid phase, more significant for 7-propylpuerarin than for 4'-propylpuerarin according to the calculated water/lipid partition coefficients, becomes important for the chain-breaking action in lipid oxidation of the puerarin derivatives as models for (iso)flavonoids and their glycosides.

Anti-oxidative and TNF-α suppressive activities of puerarin derivative (4AC) in RAW264.7 cells and collagen-induced arthritic rats

Puerarin is a major active ingredient extracted from the root of P. lobata, a traditional Chinese herb, and possesses anti-oxidative and anti-inflammatory activities. However, the low oral bioavailability of puerarin limits its further application. Therefore, we synthesized tetraacetyl puerarin (4AC) through acetylation to improve its liposolubility and bioavailability. In the present investigations, we tested the anti-oxidative and TNF-α suppressive activity of 4AC in lipopolysaccharide (LPS)-induced RAW264.7 macrophages and bovine type II collagen-induced arthritic (CIA) rats. The results showed that 4AC retained the bioactivity of puerarin. And 4AC significantly increased the activity of SOD and reduced the level of MDA both in vitro and in vivo. It also improved the level of GSH-PX and the total antioxidant capacity in vivo. Furthermore, it dramatically decreased TNF-α level in the cultured supernatant of RAW264.7 cells treated with LPS and in the serum of CIA rats. These initial results indicated that 4AC had a potential therapeutic effect on CIA rats through an anti-oxidative and TNF-α suppressive activity. In addition, the molecular mechanism of anti-oxidation of 4AC was explored by testing the MAPKs/NF-κB signaling pathway. The results showed that 4AC significantly inhibited NF-κB expression and down-regulated the levels of p-ERK and p-JNK in LPS-activated RAW264.7 cells. These results indicated that 4AC had bioactive anti-oxidative effects and suggest the potential value of 4AC for the treatment of rheumatoid arthritis.

The synthesis of puerarin derivatives and their protective effect on the myocardial ischemia and reperfusion injury

Puerarin is a naturally occurring isoflavone and is frequently used for the treatment of cardiovascular symptoms in China. By the structural modification of the puerarin molecule at different positions, seven new puerarin derivatives were obtained, and their cardioprotective activities (in vitro and in vivo) were respectively evaluated. The finding that the activities of 3 and 8 markedly exceeded puerarin suggested that the acylated modification of phenolic hydroxyl at C-7 in the puerarin molecule may improve the cardioprotective activity, which will be an important reference for further structural optimization.

Identification and antioxidative properties of transglycosylated puerarins synthesised by an archaeal maltogenic amylase

Puerarin is helpful for the prevention and treatment of various cardiovascular diseases. However, its insolubility often limits its uses. Transglycosylation reaction between 1% puerarin and 10% β-CD was catalysed by maltogenic amylase from archaeon Thermofilum pendens (TfMA) at 0.2 U/mg β-CD, 90 °C and pH 5.5, for 1 h in order to obtain puerarin glucosides of high water solubility. Seven puerarin derivatives with different number of additional α-glucosyl in the reaction solution were identified by HPLC–UV–MS analysis. Although less than puerarin, the transglycosylated puerarins still fully maintained their antioxidant activities, assessed by a radical scavenging test and a reducing power assay. Therefore, the transglycosylated puerarins exhibit a greater potential to be developed into new medicines and foods. This is the first report on the flavonoids glycosylation using the transglycosylation activity of archaeal maltogenic amylase.

Puerarin for Acute Ischemic Stroke

Graeme J. Hankey MD, FRCP Section Editor: Puerarin, a form of herbal medicine, is widely used in the treatment of acute ischemic stroke in China, but its efficacy is uncertain. The objective of this review was to assess the efficacy and safety of puerarin in patients with acute ischemic stroke. The primary objective was to determine whether puerarin improves functional outcome without causing undue harm in patients with acute ischemic stroke. The secondary objective was to assess the adverse events and quality of life. We searched the Cochrane Stroke Group Trials Register (last searched August 2006), the Trials Register of the Cochrane Complementary Medicine Field (last searched June 2006), and the Chinese Stroke Trials Register (last searched June …

Synthesis of a Novel Type of Phosphates of Puerarin

AbstractA novel type of phosphated puerarin derivatives were synthesized through a simplified Atheron‐Todd reaction for the first time. The structure of these compounds were elucidated by IR, ESI‐MS and NMR. Moreover, the reason the dialkylphophite reagent had different chemselectivities toward different hydroxys on the puerarin was discussed.