Phenylpropionic Acid Derivatives Research Articles

Plumeriapropionics A-E, Carboxyl-Substituted Phenylpropionic Acid Derivatives with Anti-Inflammatory Activity from Plumeria rubra L.

Five rare carboxyl-substituted phenylpropionic acid derivatives, plumeriapropionics A-E (1-5), together with one known analog, cerberic acid B (6), were isolated from flowers of Plumeria rubra L. Their structures were elucidated using comprehensive spectroscopic methods. To date, only one compound of this structural type has been reported. The inhibitory activities of compounds 1-6 against nitric oxide (NO) production induced by lipopolysaccharide (LPS) were evaluated in vitro using mouse macrophage RAW264.7 cells. Compounds 1-6 showed remarkable inhibitory activities on NO production, with IC50 values in the range of 6.52 ± 0.23 to 35.68 ± 0.17 µM. These results indicate that the discovery of carboxyl-substituted phenylpropionic acid derivatives from the flowers of P. rubra, which show significant anti-inflammatory properties, could be of great importance for the research and development of novel natural anti-inflammatory agents.

A New Sesquiterpene and Two Nitro-containing Phenylpropionic Acid Derivatives from the Fungus Aspergillus terreus LPFH-1

A New Sesquiterpene and Two Nitro-containing Phenylpropionic Acid Derivatives from the Fungus Aspergillus terreus LPFH-1

Exploiting Underutilised crops

Exploiting Underutilised crops

Screening of potent α-glucosidase inhibitory and antioxidant polyphenols in Prunella vulgaris L. by bioreaction-HPLC-quadrupole-time-of-flight-MS/MS and in silico analysis.

Prunella vulgaris L. is a well-known traditional Chinese medicine for blood glucose homeostasis and antioxidant potential. Ethyl acetate fraction of P. vulgaris L. demonstrated higher phenolic content (85.53 ± 6.74mg gallic acid equivalents per gram dry weight), α-glucosidase inhibitory (IC50 , 69.13 ± 2.86 μg/ml), and antioxidant (IC50 , 8.68 ± 1.01 μg/ml) activities. However, the bioactive polyphenols responsible for the beneficial properties remain unclear. Here, bioreaction-HPLC-quadrupole-time-of-flight-MS/MS method was developed for rapid, accurate, and efficient screening and identification of polyphenols with α-glucosidase inhibitory and antioxidant activities from P. vulgaris L. Bioactive polyphenols can specifically bind with α-glucosidase or react with 1,1-diphenyl-2-picryl-hydrazyl radical, which was easily discriminated from nonactive compounds. Subsequently, 20 bioactive polyphenols (16 phenyl propionic acid derivatives and four flavonoids) were screened and identified. Furthermore, molecular docking analysis revealed that screened 20 polyphenols bind with the active sites of α-glucosidase through hydrogen bonding and π-π stacking. Density functional theory calculations demonstrated their electron transport ability and chemical reactivity. The in silico analysis confirmed the screened results. In summary, this study provided a valuable strategy for rapid discovering bioactive compounds from complex natural products and offered scientific evidence for further development and application of P. vulgaris L.

Gut microbiota metabolism and the permeability of natural products contained in infusions from herb of European goldenrod Solidago virgaurea L.

Ethnopharmacological relevanceSolidago virgaurea L. (also known as European goldenrod) is a pharmacopoeial plant material popularly used by patients in the form of an infusion. It was traditionally used in Europe and North America for the treatment of urinary tract conditions. It is also reported as a topical agent for skin disorders. Aim of the studyGut microbiota metabolism plays a crucial role in the bioavailability of natural products contained in plant extracts taken orally. The aim of the current study was to establish the biotransformation of compounds contained in an infusion from goldenrod using human and piglet fecal microbiota in vitro. The permeability of unmetabolized natural products and gut microbiota metabolites was evaluated using a Caco-2 cell model. Preliminary anti-inflammatory assays of raw extract using human neutrophils were also established. Material and methodsAn infusion was prepared from Solidaginis virgaureae herba commercially available on the market. The characterization of the raw extract was performed by UHPLC-DAD-MS method. The infusion was incubated with human or swine fecal samples in anaerobic conditions. Metabolism products were analyzed and identified by UHPLC-DAD-MS technique. The permeability of the natural products contained in the raw infusion and after metabolism was checked by UHPLC method. The influence of raw extracts on proinflammatory functions of human neutrophils after LPS stimulation was established by flow cytometry and ELISA. ResultsThe experiments showed that goldenrod infusion contains mainly caffeoylquinic acid derivatives, flavonoids, and some phenylpropanoids. Natural products present in the extract were transformed by human and swine microbiota to smaller molecules mainly phenylpropanoid acid derivatives. The permeability assays showed that most of the parental compound present in the infusion cannot cross the gut epithelial barrier. In contrast, metabolites were able to cross the Caco-2 monolayer. Depending on the structure, different possible mechanisms of transport were observed. The infusion did not significantly influence the proinflammatory functions of human neutrophils. ConclusionsFollowing oral administration of goldenrod infusion, phytochemicals are prone to undergoing metabolism by gut microbiota to smaller phenylpropionic acid derivatives that can be bioavailable after crossing the gut epithelial barrier to be further metabolized and distributed. Detected metabolites should be considered as potentially active compounds responsible for the bioactivity of the raw plant material in vivo.

Sulfane transalkylations and metal catalyzed allylic substitutions for the synthesis of composite macrobicyclic peptides

A phenylpropionic acid derivative harboring two acylated cinnamyl alcohol motifs reacts with functionalized peptides during two or three-step sequences to afford macro-bicyclic products. The chemistry exploits sulfane transalkylations and transition metal catalyzed allylic aminations to generate complex ring systems scaffolded by atypical linkages to cysteine and histidine residues.

Design, synthesis, and evaluation of a series of novel phenylpropanoic acid derivatives agonists for the FFA1.

Free fatty acid 1 (FFA1/GPR40) has attracted extensive attention as a novel target for the treatment of type 2 diabetes for its role in the enhancement of insulin secretion with glucose dependency. Aiming to develop novel potent FFA1 agonists, a new series of phenylpropionic acid derivatives were designed and synthesized on the basis of the modification of chemical cement of TAK-875, AMG-837, and LY2881835. Among them, most promising compounds 7, 14, and 15 were obtained with EC50 values of 82, 79, and 88nM, exhibiting a powerful agonistic activity compared to TAK-875 (95.1nM). During Oral glucose tolerance test in normal mice, compound 7, 14, and 15 had significant glucose-lowering effect at the dose of 50mg/kg. Furthermore, compound 15 (50mg/kg) also significantly improved in glucose tolerance in type 2 diabetic mice. Herein, we reported the discovery and optimization of a series of potent FFA1 agonists. The discovery supported further exploration surrounding this scaffold.

Design, synthesis, and biological evaluation of deuterated phenylpropionic acid derivatives as potent and long-acting free fatty acid receptor 1 agonists

The free fatty acid receptor 1 (FFA1) is a potential target due to its function in enhancement of glucose-stimulated insulin secretion. Takeda’s compound 1 has robustly in vitro activity for FFA1, but it has been suffered from poor pharmacokinetic (PK) profiles because the phenylpropanoic acid is vulnerable to β-oxidation. To identify orally available agonists, we tried to interdict the metabolically labile group by incorporating two deuterium atoms at the α-position of phenylpropionic acid. Interestingly, the differences of physicochemical properties between hydrogen and deuterium are quite small, but there are many differences in the structure-activity relationship between phenylpropionic acid series and present deuterated series. Further optimizations of deuterated series led to the discovery of compound 18, which exhibited a superior balance in terms of in vitro activity, lipophilicity, and solubility. Better still, compound 18 revealed a lower clearance (CL = 0.44 L/h/kg), higher maximum concentration (Cmax = 7584.27 μg/L), and longer half-life (T1/2 = 4.16 h), resulting in a >23-fold exposure than compound 1. In subsequent in vivo pharmacodynamic studies, compound 18 showed a robustly glucose-lowering effect in rodent without the risk of hypoglycemia.

Structure Property Relationships of Carboxylic Acid Isosteres.

The replacement of a carboxylic acid with a surrogate structure, or (bio)-isostere, is a classical strategy in medicinal chemistry. The general underlying principle is that by maintaining the features of the carboxylic acid critical for biological activity, but appropriately modifying the physicochemical properties, improved analogs may result. In this context, a systematic assessment of the physicochemical properties of carboxylic acid isosteres would be desirable to enable more informed decisions of potential replacements to be used for analog design. Herein we report the structure–property relationships (SPR) of 35 phenylpropionic acid derivatives, in which the carboxylic acid moiety is replaced with a series of known isosteres. The data set generated provides an assessment of the relative impact on the physicochemical properties that these replacements may have compared to the carboxylic acid analog. As such, this study presents a framework for how to rationally apply isosteric replacements of the carboxylic acid functional group.

Wheat bran promotes enrichment within the human colonic microbiota of butyrate-producing bacteria that release ferulic acid.

SummaryCereal fibres such as wheat bran are considered to offer human health benefits via their impact on the intestinal microbiota. We show here by 16S rRNA gene‐based community analysis that providing amylase‐pretreated wheat bran as the sole added energy source to human intestinal microbial communities in anaerobic fermentors leads to the selective and progressive enrichment of a small number of bacterial species. In particular, OTUs corresponding to uncultured Lachnospiraceae (Firmicutes) related to E ubacterium xylanophilum and B utyrivibrio spp. were strongly enriched (by five to 160 fold) over 48 h in four independent experiments performed with different faecal inocula, while nine other Firmicutes OTUs showed > 5‐fold enrichment in at least one experiment. Ferulic acid was released from the wheat bran during degradation but was rapidly converted to phenylpropionic acid derivatives via hydrogenation, demethylation and dehydroxylation to give metabolites that are detected in human faecal samples. Pure culture work using bacterial isolates related to the enriched OTUs, including several butyrate‐producers, demonstrated that the strains caused substrate weight loss and released ferulic acid, but with limited further conversion. We conclude that breakdown of wheat bran involves specialist primary degraders while the conversion of released ferulic acid is likely to involve a multi‐species pathway.

Design, synthesis and evaluation of potent G-protein coupled receptor 40 agonists

Abstract GPR40 has emerged as an attractive drug target for the treatment of type 2 diabetes due to its role in the enhancement of insulin secretion with glucose dependency. With the aim to improve the metabolic and safety profiles, a series of novel phenylpropionic acid derivatives were synthesized. Extensive structural optimization led to identification of compounds 22g and 23e as potent GPR40 agonists with moderate liver microsomal stability. All the discovery supported further exploration surrounding this scaffold.

Structure–activity relationship study on benzoic acid part of diphenylamine-based retinoids

Based on structure–activity relationship studies of the benzoic acid part of diphenylamine-based retinoids, the potent RXR agonist 4 was derivatized to obtain retinoid agonists, synergists, and an antagonist. Cinnamic acid derivatives 5 and phenylpropionic acid derivatives 6 showed retinoid agonistic and synergistic activities, respectively. The difference of the activities is considered to be due to differences in the flexibility of the carboxylic acid-containing substituent on the diphenylamine skeleton. Compound 7, bearing a methyl group at the meta position to the carboxyl group, was an antagonist, dose-dependently inhibiting HL-60 cell differentiation induced by 3.3×10−10M Am80.

Improved synthesis of rupintrivir.

An improved synthesis of rupintrivir (AG7088) was accomplished using three amino acids (l-glutamic acid, d-4-fluorophenylalanine, and l-valine) as the building blocks. The key fragment ketomethylene dipeptide isostere was constructed with the valine derivative and phenylpropionic acid derivative, followed by coupling with a lactam derivative and an isoxazole acid chloride to provide AG7088 totally in eight steps.

Crystal structure and electronic properties of three phenylpropionic acid derivatives: A combined X-ray powder diffraction and quantum mechanical study

Crystal structures of three derivatives of phenylpropionic acid, 2, 3 and 4 with hydroxyl, methyl and methoxy substitutions at the 2, 4 positions have been determined from X-ray powder diffraction data and their electronic structures were calculated at the DFT level. The optimized molecular geometries agree closely to that obtained from the crystallographic analysis. Intermolecular O–H…O hydrogen bonds generate R22(8) rings, which are further connected through O–H…O and C–H…O hydrogen bonds into two-dimensional framework in 2 and 4, and a step like architecture in 3. The HOMO–LUMO energy gap (>4.0eV) indicates a high kinetic stability of the three compounds.

Dihydroxylated phenolic acids derived from microbial metabolism reduce lipopolysaccharide-stimulated cytokine secretion by human peripheral blood mononuclear cells

Oligomers and polymers of flavan-3-ols (proanthocyanidins) are very abundant in the Mediterranean diet, but are poorly absorbed. However, when these polyphenols reach the colon, they are metabolised by the intestinal microbiota into various phenolic acids, including phenylpropionic, phenylacetic and benzoic acid derivatives. Since the biological properties of these metabolites are not completely known, in the present study, we investigated the effect of the following microbial phenolic metabolites: 3,4-dihydroxyphenylpropionic acid (3,4-DHPPA), 3-hydroxyphenylpropionic acid, 3,4-dihydroxyphenylacetic acid (3,4-DHPAA), 3-hydroxyphenylacetic acid, 4-hydroxybenzoic acid and 4-hydroxyhippuric acid (4-HHA), on modulation of the production of the main pro-inflammatory cytokines (TNF-alpha, IL-1beta and IL-6). The production of these cytokines by lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC) pre-treated with the phenolic metabolites was studied in six healthy volunteers. With the exception of 4-HHA for TNF-alpha secretion, only the dihydroxylated compounds, 3,4-DHPPA and 3,4-DHPAA, significantly inhibited the secretion of these pro-inflammatory cytokines in LPS-stimulated PBMC. Mean inhibition of the secretion of TNF-alpha by 3,4-DHPPA and 3,4-DHPAA was 84.9 and 86.4 %, respectively. The concentrations of IL-6 in the culture supernatant were reduced by 88.8 and 92.3 % with 3,4-DHPPA and 3,4-DHPAA pre-treatment, respectively. Finally, inhibition was slightly higher for IL-1beta, 93.1 % by 3,4-DHPPA and 97.9 % by 3,4-DHPAA. These results indicate that dihydroxylated phenolic acids derived from microbial metabolism present marked anti-inflammatory properties, providing additional information about the health benefits of dietary polyphenols and their potential value as therapeutic agents.

Human Fecal Water Inhibits COX-2 in Colonic HT-29 Cells: Role of Phenolic Compounds

The inducible enzyme cyclooxygenase-2 (COX-2) plays a major role in the regulation of inflammation and possibly in the development of colon cancer. The aim of the present study was to screen for COX-2 inhibitors in samples of fecal water (the aqueous phase of feces) and investigate whether phenolic compounds are responsible for any observed effects on COX-2. Volunteers (n = 20) were recruited and asked to supply a 24-h stool sample. Fecal water samples were prepared and analyzed by GC-MS for their content of phenolic compounds. These samples were also evaluated for their effects on COX-2 protein levels (Western blot) and prostaglandin (PG)E2 production in tumor necrosis-alpha-stimulated HT-29 cells and pure enzymatic activity in a COX-2-catalyzed prostaglandin biosynthesis in vitro assay. The major phenolic compounds identified were phenylpropionic acid, phenylacetic acid, cinnamic acid, and benzoic acid derivatives. Of 13 fecal water samples analyzed, 12 significantly decreased PGE2 production (range 5.4-39.7% inhibition, P-value < 0.05) compared with control cells and 13 of 14 samples analyzed decreased COX-2 protein levels in HT-29 cells (19-63% inhibition). Of the 20 fecal water samples, 2 also weakly inhibited enzymatic activity of purified COX-2 (22-24% inhibition). Three compounds identified in fecal water, 3-phenylpropionic acid, 3-hydroxyphenylacetic acid, and 3-(4-hydroxyphenyl)-propionic acid, decreased the protein level at 250 micromol/L (15-62% inhibition). This study shows for the first time that human fecal water contains components that can affect both the COX-2 protein level and enzymatic activity.

Metabolism of dietary procyanidins in rats.

Procyanidins are major dietary polyphenols made of elementary flavan-3-ol (epi)catechin units. They have antioxidant properties and may contribute to health benefits in humans, but little is known about their metabolic fate. We compared here the metabolism of procyanidin dimer B3, trimer C2, and polymer isolated from willow tree catkins to that of catechin monomer in rats. These compounds were administered in the rat diet (0.1%, w/w) for 5 d and their metabolites estimated in 24 h urine. In rats fed procyanidins, neither parent compound nor catechin derivatives could be detected in contrast to animals fed catechin monomer, which excreted large amounts of catechin and its 3'-O-methylated form (25.7 +/- 0.6%). On the other hand, 16 metabolites of microbial origin were detected and identified as phenylvaleric, phenylpropionic, phenylacetic, and benzoic acid derivatives. Their total yields significantly decreased from the catechin monomer (10.6 +/- 1.1%) to the procyanidin dimer (6.5 +/- 0.2%), trimer (0.7 +/- 0.1%), and polymer (0.5 +/- 0.1%). Therefore, the degree of procyanidin polymerization has a major impact on their fate in the body characterized by a poor absorption through the gut barrier and a limited metabolism by the intestinal microflora as compared to catechin. This will have to be considered to explain the health effects of procyanidins. The contribution of their microbial metabolites should also be further investigated.

Interaction of N-benzoyl-D-phenylalanine and related compounds with the sulphonylurea receptor of beta-cells.

1. The structure activity relationships for the insulin secretagogues N-benzoyl-D-phenylalanine (NBDP) and related compounds were examined at the sulphonylurea receptor level by use of cultured HIT-T15 and mouse pancreatic beta-cells. The affinities of these compounds for the sulphonylurea receptor were compared with their potencies for K(ATP)-channel inhibition. In addition, the effects of cytosolic nucleotides on K(ATP)-channel inhibition by NBDP were investigated. 2. NBDP displayed a dissociation constant for binding to the sulphonylurea receptor (K(D) value) of 11 microM and half-maximally effective concentrations of K(ATP)-channel inhibition (EC50 values) between 2 and 4 microM (in the absence of cytosolic nucleotides or presence of 0.1 mM GDP or 1 mM ADP). 3. In the absence of cytosolic nucleotides or presence of GDP (0.1 mM) maximally effective concentrations of NBDP (0.1-1 mM) reduced K(ATP)-channel activity to 47% and 44% of control, respectively. In the presence of ADP (1 mM), K(ATP)-channel activity was completely suppressed by 0.1 mM NBDP. 4. The L-isomer of N-benzoyl-phenylalanine displayed a 20 fold lower affinity and an 80 fold lower potency than the D-isomer. 5. Introduction of a p-nitro substituent in the D-phenylalanine moiety of NBDP did not decrease lipophilicity but lowered affinity and potency by more than 30 fold. 6. Introduction of a p-amino substituent in the D-phenylalanine moiety of NBDP (N-benzoyl-p-amino-D-phenylalanine, NBADP) reduced lipophilicity and lowered affinity and potency by about 10 fold. This loss of affinity and potency was compensated for by formation of the phenylpropionic acid derivative of NBADP. A similar difference in affinity was observed for the sulphonylurea carbutamide and its phenylpropionic acid derivative. 7. Replacing the benzene ring in the D-phenylalanine moiety of NBDP by a cyclohexyl ring increased lipophilicity, and the K(D) and EC50 values were slightly lower than for NBDP. Exchange of both benzene rings in NBDP by cyclohexyl rings further increased lipophilicity without altering affinity and potency. 8. This study shows that N-acylphenylalanines interact with the sulphonylurea receptor of pancreatic beta-cells in a stereospecific manner. Their potency depends on lipophilic but not aromatic properties of their benzene rings. As observed for sulphonylureas, interaction of N-acylphenylalanines with the sulphonylurea receptor does not induce complete inhibition of K(ATP)-channel activity in the absence of inhibitory cytosolic nucleotides.

Identification of Gingko biloba flavonol metabolites after oral administration to humans.

An extract of Ginkgo biloba leaves (EGb) was given to healthy volunteers. Urine samples were collected for 3 days, and blood samples were withdrawn every 30 min for 5 h. The samples were purified through SPE C18 cartridges and analyzed by reversed-phase LC-diode array detection for the presence of EGb metabolites. Only urine samples contained detectable amounts of substituted benzoic acids, i.e., 4-hydroxybenzoic acid conjugate, 4-hydroxyhippuric acid, 3-methoxy-4-hydroxyhippuric acid, 3,4-dihydroxybenzoic acid, 4-hydroxybenzoic acid, hippuric acid and 3-methoxy-4-hydroxybenzoic acid (vanillic acid). In contrast to rats no phenylacetic acid or phenylpropionic acid derivatives were found in urine, thus indicating that in humans a more extensive metabolism takes place. As for rats the metabolites found in human urines accounted for less than 30% of the flavonoids given. The same procedure was applied to blood samples, and no metabolites could be detected.

1-(5-Dimethylamino-1-naphthalenesulphonyl)-(S)-3-aminopyrrolidine (DNS-Apy) as a fluorescence chiral labelling reagent for carboxylic acid enantiomers.

1-(5-Dimethylamino-1-naphthalenesulphonyl)-(S)-3-aminopyrrolidi ne (DNS-Apy) has been synthesized for the separation of carboxylic acid enantiomers by high-performance liquid chromatography (HPLC) and sensitive detection. The reagent reacts with carboxylic acids at room temperature in the presence of activation agents 2,2'-dipyridyl disulphide (DPDS) and triphenylphosphine (TPP). The maximum emission of the diastereomeric amide derived from (S)-phenylpropionic acid and ketoprofen derivatives of DNS-Apy was at 530 nm with excitation at 340 nm. The emission wavelength shifted towards the blue and the fluorescence intensities increased with increasing acetonitrile concentration in the medium. The diastereomers derived from anti-inflammatory drugs were efficiently resolved with a reverse-phase column using water:acetonitrile mixture as mobile phase. All of the racemate of arylpropionic acid derivatives gave equal fluorescence intensity of the two enantiomers with the exception of ketoprofen derivatives where the intensity of the first eluting enantiomer was half that of the second.