Trityl Cation-Catalyzed Hosomi-Sakurai Reaction of Allylsilane with β,γ-Unsaturated α-Ketoester to Form γ,γ-Disubstituted α-Ketoesters

(Ph₃C)[BPh(^F)₄]-catalyzed Hosomi-Sakurai allylation of allylsilanes with β,γ-unsaturated α-ketoesters has been developed to give γ,γ-disubstituted α-ketoesters in high yields with excellent chemoselectivity. Preliminary mechanistic studies suggest that trityl cation dominates the catalysis, while the silyl cation plays a minor role.     

Reductive Methylation of Homogeneous Primary β-Lauryl/myristyl 7/3 Polyethyleneoxy n = 3–18 Ethylamines under Phase-Transfer Catalysis Conditions

Homogeneous tertiary N,N-dimethyl-N-β-lauryl/myristyl 7/3 polyethyleneoxy n = 3–18 ethylamines, LM(EO)_nAT, are niche intermediates in the synthesis of homogeneous N-alkyl (C₁–C₁₈)-N,N-dimethyl-N-β-lauryl/myristyl 7/3 polyethyleneoxy n = 3–18 ethylammonium chlorides (unitary degree of oligomerization of ethylene oxide in the polyoxyethylene chain). This paper synthetically presents the dependence of the reductive methylation yields of homogeneous primary β-lauryl/myristyl 7/3 polyethyleneoxy n = 3–18 ethylamines, LM(EO)_nAP, on the reaction time (10–90 min), the temperature (70 °C), the molar ratio formic aldehyde /LM(EO)_nAP (1.1/1–2.5/1), the molar ratio HCOOH/LM(EO)_nAP (5/1), the degree of oligomerization of ethylene oxide in the homogeneous polyoxyethylene chain in the 3,6,9,12,18 series, and the structure of the phase-transfer catalysts. The steric effects of hydrophobic groups CH₃ and C₁₈H₃₇ grafted onto the ammonium function, and the micellar phenomena in the vicinity of their critical micellar concentration, directly proportional to the homogeneous degree of oligomerization, were highlighted. In all cases, a steady increase in reductive methylation yields was observed, with even quantitative values obtained. The high purity of the homologous series LM(EO)_nAT will allow their personalization as reference structures for the study of the evolution of basic colloidal characteristics useful in forecasting technological applications. LM(EO)_nAP were obtained either by direct amidoethylation (nucleophilic addition under basic catalysis of homogeneous lauryl/myristyl 7/3 polyethoxylated n = 3, 6, 9, 12, 18 alcohols, LM(EO)_nOH, to acrylamide monomer) or by cyanoethylation of LM(EO)_nOH under basic catalysis at 25–50 °C, in the presence of Fe²⁺ cations as oligomerization/polymerization inhibitor, followed by partial acid hydrolysis of homogeneous β-alkyl (C₁₂H₂₅/C₁₄H₂₉) 7/3 polyethyleneoxy n = 3, 6, 9, 12, 18 propionitriles, LM(EO)_nPN, to β-alkyl (C₁₂H₂₅/C₁₄H₂₉) 7/3 polyethyleneoxy n = 3, 6, 9, 12, 18 propionamides, LM(EO)_nPD, which led to LM(EO)_nAP by Hoffmann degradation. Homogeneous higher tertiary polyetheramines LM(EO)_nAT were structurally characterized.     

α-Amyrin and β-Amyrin Isolated from Celastrus hindsii Leaves and Their Antioxidant,Anti-Xanthine Oxidase,and Anti-Tyrosinase Potentials

Celastrus hindsii is a popular medicinal plant in Vietnam and Southeast Asian countries as well as in South America. In this study, an amount of 12.05 g of an α-amyrin and β-amyrin mixture was isolated from C. hindsii (10.75 g/kg dry weight) by column chromatography applying different solvent systems to obtain maximum efficiency. α-Amyrin and β-amyrin were then confirmed by gas chromatography-mass spectrometry (GC-MS), electrospray ionization-mass spectrometry (ESI-MS), and nuclear magnetic resonance (NMR). The antioxidant activities of the α-amyrin and β-amyrin mixture were determined via 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,20-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays with IC₅₀ of 125.55 and 155.28 µg/mL, respectively. The mixture exhibited a high potential for preventing gout by inhibiting a relevant key enzyme, xanthine oxidase (XO) (IC₅₀ = 258.22 µg/mL). Additionally, an important enzyme in skin hyperpigmentation, tyrosinase, was suppressed by the α-amyrin and β-amyrin mixture (IC₅₀ = 178.85 µg/mL). This study showed that C. hindsii is an abundant source for the isolation of α-amyrin and β-amyrin. Furthermore, this was the first study indicating that α-amyrin and β-amyrin mixture are promising in future therapies for gout and skin hyperpigmentation.     

Sterically Demanding Unsymmetrical Diaryl-λ3-iodanes for Electrophilic Pentafluorophenylation and an Approach to α-Pentafluorophenyl Carbonyl Compounds with an All-Carbon Stereocenter

A sterically demanding unsymmetrical pentafluorophenyl-triisopropylphenyl-λ³-iodane was developed as an effective reagent for the electrophilic pentafluorophenylation of various β-keto esters and a β-keto amide. 17 examples of α-pentafluorophenylated 1,3-dicarbonyl compounds 3 having a quaternary carbon center are provided. The resulting compounds were nicely transformed into chiral α-pentafluorophenyl ketones with an all-carbon stereogenic center in high yields and high enantioselectivities using asymmetric organocatalysis (up to 98 % ee) or asymmetric metal catalysis (up to 82 % ee).     

Chemical Constituents from the Leaves of Ligustrum robustum and Their Bioactivities

The leaves of Ligustrum robustum have been consumed as Ku-Ding-Cha for clearing heat and removing toxins, and they have been used as a folk medicine for curing hypertension, diabetes, and obesity in China. The phytochemical research on the leaves of L. robustum led to the isolation and identification of two new hexenol glycosides, two new butenol glycosides, and five new sugar esters, named ligurobustosides X (1a), X₁ (1b), Y (2a), and Y₁ (2b) and ligurobustates A (3a), B (3b), C (4b), D (5a), and E (5b), along with seven known compounds (4a and 6–10). Compounds 1–10 were tested for their inhibitory effects on fatty acid synthase (FAS), α-glucosidase, and α-amylase, as well as their antioxidant activities. Compound 2 showed strong FAS inhibitory activity (IC₅₀ 4.10 ± 0.12 μM) close to that of the positive control orlistat (IC₅₀ 4.46 ± 0.13 μM); compounds 7 and 9 revealed moderate α-glucosidase inhibitory activities; compounds 1–10 showed moderate α-amylase inhibitory activities; and compounds 1 and 10 displayed stronger 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) ammonium salt (ABTS) radical scavenging effects (IC₅₀ 3.41 ± 0.08~5.65 ± 0.19 μM) than the positive control l-(+)-ascorbic acid (IC₅₀ 10.06 ± 0.19 μM). This study provides a theoretical foundation for the leaves of L. robustum as a functional tea to prevent diabetes and its complications.     

Synthesis of Mono-Amino Substituted γ-CD: Host–Guest Complexation and In Vitro Cytotoxicity Investigation

Cyclodextrins (CDs) are cyclic oligosaccharides which can trap hydrophobic molecules and improve their chemical, physical, and biological properties. γ-CD showed the highest aqueous solubility with the largest cavity diameter among other CD types. The current study describes a direct and easy method for nucleophilic mono-aminos to be substituted with γ-CD and tested for their ability to host the guest curcumin (CUR) as a hydrophobic drug model. The mass spectrometry and NMR analyses showed the successful synthesis of three amino-modified γ-CDs: mono-6-amino-6-deoxy-cyclodextrine (γ-CD-NH₂), mono-6-deoxy-6-ethanolamine-γ-cyclodextrine (γ-CD-NHCH₂CH₂OH), and mono-6-deoxy-6-aminoethylamino)-γ-cyclodextrin (γ-CD-NHCH₂CH₂NH₂). These three amino-modified γ-CDs were proven to be able to host CUR as native γ-CDs with formation constants equal to 6.70 ± 1.02, 5.85 ± 0.80, and 8.98 ± 0.90 mM⁻¹, respectively. Moreover, these amino-modified γ-CDs showed no significant toxicity against human dermal fibroblast cells. In conclusion, the current work describes a mono-substitution of amino-modified γ-CDs that can still host guests and showed low toxicity in human dermal fibroblasts cells. Therefore, the amino-modified γ-CDs can be used as a carrier host and be conjugated with a wide range of molecules for different biomedical applications, especially for active loading methods.     

Palladium-catalyzed asymmetric allylic alkylation (AAA) with alkyl sulfones as nucleophiles

An efficient palladium-catalyzed AAA reaction with a simple α-sulfonyl carbon anion as nucleophiles is presented for the first time. Allyl fluorides are used as superior precursors for the generation of π-allyl complexes that upon ionization liberate fluoride anions for activation of silylated nucleophiles. With the unique bidentate diamidophosphite ligand ligated palladium as catalyst, the in situ generated α-sulfonyl carbon anion was quickly captured by the allylic intermediates, affording a series of chiral homo-allylic sulfones with high efficiency and selectivity. This work provides a mild in situ desilylation strategy to reveal nucleophilic carbon centers that could be used to overcome the pK_a limitation of “hard” nucleophiles in enantioselective transformations.

A variety of “hard” α-sulfonyl carbanions of aryl, heteroaryl and alkyl sulfones were successfully employed as nucleophiles in palladium-catalyzed asymmetric allylic alkylation with excellent enantioselectivities.     

Bimetallic Iron–Palladium Catalyst System as a Lewis-Acid for the Synthesis of Novel Pharmacophores Based Indole Scaffold as Anticancer Agents

The Friedel–Crafts reaction between substituted indoles as nucleophiles with chalcones-based benzofuran and benzothiophene scaffolds was carried out by employing a highly efficient bimetallic iron–palladium catalyst system. This catalytic approach produced the desired bis-heteroaryl products with low catalyst loading, a simple procedure, and with acceptable yield. All synthesized indole scaffolds 3a–3s were initially evaluated for their cytotoxic effect against human fibroblast BJ cell lines and appeared to be non-cytotoxic. All non-cytotoxic compounds 3a–3s were then evaluated for their anticancer activities against cervical cancer HeLa, prostate cancer PC3, and breast cancer MCF-7 cell lines, in comparison to standard drug doxorubicin, with IC₅₀ values 1.9 ± 0.4 µM, 0.9 ± 0.14 µM and 0.79 ± 0.05 µM, respectively, and appeared to be moderate to weak anticancer agents. Fluoro-substituted chalcone moiety-containing compounds, 3b appeared to be the most active member of the series against cervical HeLa (IC₅₀ = 8.2 ± 0.2 µM) and breast MCF-7 cancer cell line (IC₅₀ = 12.3 ± 0.04 µM), whereas 6-fluroindol-4-bromophenyl chalcone-containing compound 3e (IC₅₀ = 7.8 ± 0.4 µM) appeared to be more active against PC3 prostate cancer cell line.     

Synthesis of Novel N-Methylmorpholine-Substituted Benzimidazolium Salts as Potential α-Glucosidase Inhibitors

The α-glucosidase enzyme, located in the brush border of the small intestine, is responsible for overall glycemic control in the body. It hydrolyses the 1,4-linkage in the carbohydrates to form blood-absorbable monosaccharides that ultimately increase the blood glucose level. α-Glucosidase inhibitors (AGIs) can reduce hydrolytic activity and help to control type 2 diabetes. Aiming to achieve this, a novel series of 1-benzyl-3-((2-substitutedphenyl)amino)-2-oxoethyl)-2-(morpholinomethyl)-1H-benzimidazol-3-ium chloride was synthesized and screened for its α-glucosidase inhibitory potential. Compounds 5d, 5f, 5g, 5h and 5k exhibited better α-glucosidase inhibitions compared to the standard drug (acarbose IC₅₀ = 58.8 ± 0.012 µM) with IC₅₀ values of 15 ± 0.030, 19 ± 0.060, 25 ± 0.106, 21 ± 0.07 and 26 ± 0.035 µM, respectively. Furthermore, the molecular docking studies explored the mechanism of enzyme inhibitions by different 1,2,3-trisubstituted benzimidazolium salts via significant ligand–receptor interactions.     

Hydrogenation of β-Keto Sulfones to β-Hydroxy Sulfones with Alkyl Aluminum Compounds: Structure of Intermediate Hydroalumination Products

β-Hydroxy sulfones are important in organic synthesis. The simplest method of β-hydroxy sulfones synthesis is the hydrogenation of β-keto sulfones. Herein, we report the reducing properties of alkyl aluminum compounds R₃Al (R = Et, i-Bu, n-Bu, t-Bu and n-Hex); i-Bu₂AlH; Et₂AlCl and EtAlCl₂ in the hydrogenation of β-keto sulfones. The compounds i-Bu₂AlH, i-Bu₃Al and Et₃Al are the at best reducing agents of β-keto sulfones to β-hydroxy sulfones. In reactions of β-keto sulfones with aluminum trialkyls, hydroalumination products with β-hydroxy sulfone ligands [R₂AlOC(C₆H₅)CH₂S(O)₂(p-R¹C₆H₄]_n [where n = 1,2; 2aa: R = i-Bu, R¹ = CH₃; 2ab: R = i-Bu, R¹ = Cl; 2ba: R = Et, R¹ = CH₃; 2bb: R = Et, R¹ = Cl] and {[Et₂AlOC(C₆H₅)CH₂S(O)₂(p-ClC₆H₄]∙Et₃Al}_n 3bb were obtained. These complexes in the solid state have a dimeric structure, while in solutions, they appear as equilibrium monomer–dimer mixtures. The hydrolysis of both the isolated 2aa, 2ab, 2ba, 2bb and 3bb and the postreaction mixtures quantitatively leads to pure racemic β-hydroxy sulfones. Hydroalumination reaction of β-keto sulfones with alkyl aluminum compounds and subsequent hydrolysis of the complexes is a simple and very efficient method of β-hydroxy sulfones synthesis.     

The Amyloid Fibril-Forming β-Sheet Regions of Amyloid β and α-Synuclein Preferentially Interact with the Molecular Chaperone 14-3-3ζ

14-3-3 proteins are abundant, intramolecular proteins that play a pivotal role in cellular signal transduction by interacting with phosphorylated ligands. In addition, they are molecular chaperones that prevent protein unfolding and aggregation under cellular stress conditions in a similar manner to the unrelated small heat-shock proteins. In vivo, amyloid β (Aβ) and α-synuclein (α-syn) form amyloid fibrils in Alzheimer’s and Parkinson’s diseases, respectively, a process that is intimately linked to the diseases’ progression. The 14-3-3ζ isoform potently inhibited in vitro fibril formation of the 40-amino acid form of Aβ (Aβ₄₀) but had little effect on α-syn aggregation. Solution-phase NMR spectroscopy of ¹⁵N-labeled Aβ₄₀ and A53T α-syn determined that unlabeled 14-3-3ζ interacted preferentially with hydrophobic regions of Aβ₄₀ (L11-H21 and G29-V40) and α-syn (V3-K10 and V40-K60). In both proteins, these regions adopt β-strands within the core of the amyloid fibrils prepared in vitro as well as those isolated from the inclusions of diseased individuals. The interaction with 14-3-3ζ is transient and occurs at the early stages of the fibrillar aggregation pathway to maintain the native, monomeric, and unfolded structure of Aβ₄₀ and α-syn. The N-terminal regions of α-syn interacting with 14-3-3ζ correspond with those that interact with other molecular chaperones as monitored by in-cell NMR spectroscopy.     

GC/MS Analysis of Essential Oil and Enzyme Inhibitory Activities of Syzygium cumini (Pamposia) Grown in Egypt: Chemical Characterization and Molecular Docking Studies

Syzygium cumini (Pomposia) is a well-known aromatic plant belonging to the family Myrtaceae, and has been reported for its various traditional and pharmacological potentials, such as its antioxidant, antimicrobial, anti-inflammatory, and antidiarrheal properties. The chemical composition of the leaf essential oil via gas chromatography–mass spectrometry (GC/MS) analysis revealed the identification of fifty-three compounds representing about 91.22% of the total oil. The identified oil was predominated by α-pinene (21.09%), followed by β-(E)-ocimene (11.80%), D-limonene (8.08%), β-pinene (7.33%), and α-terpineol (5.38%). The tested oil revealed a moderate cytotoxic effect against human liver cancer cells (HepG2) with an IC₅₀ value of 38.15 ± 2.09 µg/mL. In addition, it effectively inhibited acetylcholinesterase with an IC₅₀ value of 32.9 ± 2.1 µg/mL. Furthermore, it showed inhibitory properties against α-amylase and α-glucosidase with IC₅₀ values of 57.80 ± 3.30 and 274.03 ± 12.37 µg/mL, respectively. The molecular docking studies revealed that (E)-β-caryophyllene, one of the major compounds, achieved the best docking scores of −6.75, −5.61, and −7.75 for acetylcholinesterase, α-amylase, and α-glucosidase, respectively. Thus, it is concluded that S. cumini oil should be considered as a food supplement for the elderly to enhance memory performance and for diabetic patients to control blood glucose.     

Design and Synthesis of New Benzo[d]oxazole-Based Derivatives and Their Neuroprotective Effects on β-Amyloid-Induced PC12 Cells

A series of novel synthetic substituted benzo[d]oxazole-based derivatives (5a–5v) exerted neuroprotective effects on β-amyloid (Aβ)-induced PC12 cells as a potential approach for the treatment of Alzheimer’s disease (AD). In vitro studies show that most of the synthesized compounds were potent in reducing the neurotoxicity of Aβ_25-35-induced PC12 cells at 5 μg/mL. We found that compound 5c was non-neurotoxic at 30 μg/mL and significantly increased the viability of Aβ_25-35-induced PC12 cells at 1.25, 2.5 and 5 μg/mL. Western blot analysis showed that compound 5c promoted the phosphorylation of Akt and glycogen synthase kinase (GSK-3β) and decreased the expression of nuclear factor-κB (NF-κB) in Aβ_25-35-induced PC12 cells. In addition, our findings demonstrated that compound 5c protected PC12 cells from Aβ_25-35-induced apoptosis and reduced the hyperphosphorylation of tau protein, and decreased the expression of receptor for AGE (RAGE), β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), inducible nitric oxide synthase (iNOS) and Bcl-2-associated X protein/B-cell lymphoma 2 (Bax/Bcl-2) via Akt/GSK-3β/NF-κB signaling pathway. In vivo studies suggest that compound 5c shows less toxicity than donepezil in the heart and nervous system of zebrafish.     

Beta-Amyloid (Aβ1-42) Increases the Expression of NKCC1 in the Mouse Hippocampus

Alzheimer’s disease (AD) is a neurodegenerative disorder with an increasing need for developing disease-modifying treatments as current therapies only provide marginal symptomatic relief. Recent evidence suggests the γ-aminobutyric acid (GABA) neurotransmitter system undergoes remodeling in AD, disrupting the excitatory/inhibitory (E/I) balance in the brain. Altered expression levels of K-Cl-2 (KCC2) and N-K-Cl-1 (NKCC1), which are cation–chloride cotransporters (CCCs), have been implicated in disrupting GABAergic activity by regulating GABA_A receptor signaling polarity in several neurological disorders, but these have not yet been explored in AD. NKCC1 and KCC2 regulate intracellular chloride [Cl⁻]_i by accumulating and extruding Cl⁻, respectively. Increased NKCC1 expression in mature neurons has been reported in these disease conditions, and bumetanide, an NKCC1 inhibitor, is suggested to show potential therapeutic benefits. This study used primary mouse hippocampal neurons to explore if KCC2 and NKCC1 expression levels are altered following beta-amyloid (Aβ_1-42) treatment and the potential neuroprotective effects of bumetanide. KCC2 and NKCC1 expression levels were also examined in 18-months-old male C57BL/6 mice following bilateral hippocampal Aβ_1-42 stereotaxic injection. No change in KCC2 and NKCC1 expression levels were observed in mouse hippocampal neurons treated with 1 nM Aβ_1-42, but NKCC1 expression increased 30-days post-Aβ_1-42-injection in the CA1 region of the mouse hippocampus. Primary mouse hippocampal cultures were treated with 1 nM Aβ_1-42 alone or with various concentrations of bumetanide (1 µM, 10 µM, 100 µM, 1 mM) to investigate the effect of the drug on cell viability. Aβ_1-42 produced 53.1 ± 1.4% cell death after 5 days, and the addition of bumetanide did not reduce this. However, the drug at all concentrations significantly reduced cell viability, suggesting bumetanide is highly neurotoxic. In summary, these results suggest that chronic exposure to Aβ_1-42 alters the balance of KCC2 and NKCC1 expression in a region-and layer-specific manner in mouse hippocampal tissue; therefore, this process most likely contributes to altered hippocampal E/I balance in this model. Furthermore, bumetanide induces hippocampal neurotoxicity, thus questioning its suitability for AD therapy. Further investigations are required to examine the effects of Aβ_1-42 on KCC2 and NKCC1 expression and whether targeting CCCs might offer a therapeutic approach for AD.     

Discovery of Amide-Functionalized Benzimidazolium Salts as Potent α-Glucosidase Inhibitors

α-Glucosidase inhibitors (AGIs) are used as medicines for the treatment of diabetes mellitus. The α-Glucosidase enzyme is present in the small intestine and is responsible for the breakdown of carbohydrates into sugars. The process results in an increase in blood sugar levels. AGIs slow down the digestion of carbohydrates that is helpful in controlling the sugar levels in the blood after meals. Among heterocyclic compounds, benzimidazole moiety is recognized as a potent bioactive scaffold for its wide range of biologically active derivatives. The aim of this study is to explore the α-glucosidase inhibition ability of benzimidazolium salts. In this study, two novel series of benzimidazolium salts, i.e., 1-benzyl-3-{2-(substituted) amino-2-oxoethyl}-1H-benzo[d]imidazol-3-ium bromide 9a–m and 1-benzyl-3-{2-substituted) amino-2-oxoethyl}-2-methyl-1H-benzo[d] imidazol-3-ium bromide 10a–m were screened for their in vitro α-glucosidase inhibitory potential. These compounds were synthesized through a multistep procedure and were characterized by ¹H-NMR, ¹³C-NMR, and EI-MS techniques. Compound 10d was identified as the potent α-glucosidase inhibitor among the series with an IC₅₀ value of 14 ± 0.013 μM, which is 4-fold higher than the standard drug, acarbose. In addition, compounds 10a, 10e, 10h, 10g, 10k, 10l, and 10m also exhibited pronounced potential for α-glucosidase inhibition with IC₅₀ value ranging from 15 ± 0.037 to 32.27 ± 0.050 µM when compared with the reference drug acarbose (IC₅₀ = 58.8 ± 0.12 μM). A molecular docking study was performed to rationalize the binding interactions of potent inhibitors with the active site of the α-glucosidase enzyme.     

N-phenyl-6-chloro-4-hydroxy-2-quinolone-3-carboxamides: Molecular Docking,Synthesis, and Biological Investigation as Anticancer Agents

Cancer is a multifactorial disease and the second leading cause of death worldwide. Diverse factors induce carcinogenesis, such as diet, smoking, radiation, and genetic defects. The phosphatidylinositol 3-kinase (PI3Kα) has emerged as an attractive target for anticancer drug design. Eighteen derivatives of N-phenyl-6-chloro-4-hydroxy-2-quinolone-3-carboxamide were synthesized and characterized using FT-IR, NMR (¹H and ¹³C), and high-resolution mass spectra (HRMS). The series exhibited distinct antiproliferative activity (IC₅₀ µM) against human epithelial colorectal adenocarcinoma (Caco-2) and colon carcinoma (HCT-116) cell lines, respectively: compounds 16 (37.4, 8.9 µM), 18 (50.9, 3.3 µM), 19 (17.0, 5.3 µM), and 21 (18.9, 4.9 µM). The induced-fit docking (IFD) studies against PI3Kαs showed that the derivatives occupy the PI3Kα binding site and engage with key binding residues.     

In Vitro Evaluation of α-amylase and α-glucosidase Inhibition of 2,3-Epoxyprocyanidin C1 and Other Constituents from Pterocarpus erinaceus Poir

Diabetes mellitus is a metabolic disorder which is one of the leading causes of mortality and morbidities in elderly humans. Chronic diabetes can lead to kidney failure, blindness, limb amputation, heart attack and stroke. Physical activity, healthy diets and medications can reduce the incidence of diabetes, so the search for more efficient antidiabetic therapies, most especially from natural products, is a necessity. Herein, extract from roots of the medicinal plant Pterocarpus erinaceus was purified by column chromatography and afforded ten compounds which were characterized by EIMS, HR-FAB-MS, 1D and 2D NMR techniques. Amongst them were, a new trimeric derivative of epicatechin, named 2,3-Epoxyprocyanidin C1 (1); two pentacyclic triterpenoids, friedelin (2) and betulin (3); angolensin (4); flavonoids such as 7-methoxygenistein (5), 7-methoxydaidzein (6), apigenin 7-O-glucoronide (8) and naringenin 7-O-β-D-glucopyranoside (9); and an ellagic acid derivative (10). The extract and compounds were evaluated for their antidiabetic potential by α-amylase and α-glucosidase inhibitory assays. IC₅₀ values of compound 7 (48.1 ± 0.9 µg/mL), compound 8 (48.6 ± 0.1 µg/mL), compound 9 (50.2 ± 0.5 µg/mL) and extract (40.5 ± 0.8 µg/mL) when compared to that of acarbose (26.4 ± 0.3 µg/mL) indicated good α-amylase inhibition. In the α-glucosidase assay, the extract (IC₅₀ = 31.2 ± 0.1 µg/mL), compound 7 (IC₅₀ = 39.5 ± 1.2 µg/mL), compound 8 (IC₅₀ = 40.9 ± 1.3 µg/mL), compound 1 (IC₅₀ = 41.6 ± 1.0 µg/mL), Compound 4 (IC₅₀ = 43.4 ± 0.5 µg/mL), compound 5 (IC₅₀ = 47.6 ± 0.9 µg/mL), compound 6 (IC₅₀ = 46.3 ± 0.2 µg/mL), compound 7 (IC₅₀ = 45.0 ± 0.8 µg/mL), compound 9 (IC₅₀ = 44.8 ± 0.6 µg/mL) and compound 11 (IC₅₀ = 47.5 ± 0.4 µg/mL) all had moderate-to-good inhibitions, compared to acarbose (IC₅₀ = 22.0 ± 0.5 µg/mL). The ability to inhibit α-amylase and α-glucosidase indicates that P. erinaceus and its compounds can lower blood glucose levels by delaying hydrolysis of carbohydrates into sugars, thereby providing a source of natural antidiabetic remedy.     

Phenylethanoid and Phenylmethanoid Glycosides from the Leaves of Ligustrum robustum and Their Bioactivities

The phytochemical study on the leaves of Ligustrum robustum, which have been used as Ku-Ding-Cha, led to the isolation and identification of three new phenylethanoid glycosides and three new phenylmethanoid glycosides, named ligurobustosides R₁ (1b), R_2–3 (2), R₄ (3), S₁ (4b), S₂ (5), and S₃ (6), and five reported phenylethanoid glycosides (7–11). In the bioactivity test, (Z)-osmanthuside B₆ (11) displayed strong fatty acid synthase (FAS) inhibitory activity (IC₅₀: 4.55 ± 0.35 μM) as the positive control orlistat (IC₅₀: 4.46 ± 0.13 μM), while ligurobustosides R₄ (3) and S₂ (5), ligupurpuroside B (7), cis-ligupurpuroside B (8), ligurobustoside N (9), osmanthuside D (10), and (Z)-osmanthuside B₆ (11) showed stronger ABTS radical scavenging activity (IC₅₀: 2.68 ± 0.05~4.86 ± 0.06 μM) than the positive control L-(+)-ascorbic acid (IC₅₀: 10.06 ± 0.19 μM). This research provided a theoretical basis for the leaves of L. robustum as a tea with function in treating obesity and diabetes.     

GC-MS Studies on the Conversion and Derivatization of γ-Glutamyl Peptides to Pyroglutamate (5-Oxo-Proline) Methyl Ester Pentafluoropropione Amide Derivatives

Glutathione (γ-L-glutamyl-L-cysteinyl-glycine, γ-Glu-Cys-Gly) is the most abundant intra-cellular dicarboxylic tripeptide with multiple physiological roles. In biological samples, glutathione exists in its reduced form GSH and in two stable oxidized forms, i.e., in its symmetric disulfide form GSSG and as S-glutathionyl residue in proteins. S-Glutathionylation is a post-translational modification, which is involved in several pathophysiological processes, including oxidative stress. The GSH-to-GSSG molar ratio is widely used as a measure of oxidative stress. γ-Glutamyl is the most characteristic structural moiety of GSH. We performed gas chromatography-mass spectrometry (GC-MS) studies for the development of a highly specific qualitative and quantitative method for γ-glutamyl peptides. We discovered intra-molecular conversion of GSH, GSSG, γ-Glu-Cys and of ophthalmic acid (OPH; γ-glutamyl-α-amino-n-butyryl-glycine) to pyroglutamate (pGlu; 5-oxo-proline, also known as pidolic acid) during their derivatization with 2 M HCl/CH₃OH (60 min, 80 °C). For GC-MS analysis, the methyl esters (Me) were further derivatized with pentafluoropropionic (PFP) anhydride in ethyl acetate (1:4, v/v; 30 min, 65 °C) to their PFP derivatives. At longer reaction times, pGlu is hydrolyzed to Glu. Internal standards were prepared by derivatizing GSH, GSSG, γ-Glu-Cys and OPH in 2 M HCl/CD₃OD. Quantification of the Me-PFP derivative of pGlu was performed in the electron-capture negative-ion chemical ionization (ECNICI) mode by selected-ion monitoring (SIM) of the mass-to-charge (m/z) ions 269 for unlabeled pGlu (d₀Me-PFP-pGlu) and m/z 272 for the in situ prepared deuterium-labeled pGlu (d₃Me-PFP-pGlu). Although not inherent to the analysis of small peptides, the present GC-MS method is useful to study several biochemical aspects of GSH. Using pentafluorobenzyl bromide (PFB-Br) as the derivatization reagent, we found that synthetic pGlu is converted in aqueous acetone (60 min, 50 °C) into its pentafluorobenzyl (PFB) ester (PFB-pGlu). This derivatization procedure is useful for the GC-MS analysis of free pGlu in the ECNICI mode. Quantitative analysis of PFB-pGlu by GC-MS requires the use of stable-isotope labeled analogs of pGlu as an internal standard.     

Trifluoromethylated Flavonoid-Based Isoxazoles as Antidiabetic and Anti-Obesity Agents: Synthesis,In Vitro α-Amylase Inhibitory Activity,Molecular Docking and Structure–Activity Relationship Analysis

Diabetes mellitus is a major health problem globally. The management of carbohydrate digestion provides an alternative treatment. Flavonoids constitute the largest group of polyphenolic compounds, produced by plants widely consumed as food and/or used for therapeutic purposes. As such, isoxazoles have attracted the attention of medicinal chemists by dint of their considerable bioactivity. Thus, the main goal of this work was to discover new hybrid molecules with properties of both flavonoids and isoxazoles in order to control carbohydrate digestion. Moreover, the trifluoromethyl group is a key entity in drug development, due to its strong lipophilicity and metabolic stability. Therefore, the present work describes the condensation of a previously synthesized trifluoromethylated flavonol with different aryl nitrile oxides, affording 13 hybrid molecules indicated as trifluoromethylated flavonoid-based isoxazoles. The structures of the obtained compounds were deduced from by ¹H NMR, ¹³C NMR, and HRMS analysis. The 15 newly synthesized compounds inhibited the activity of α-amylase with an efficacy ranging from 64.5 ± 0.7% to 94.7 ± 1.2% at a concentration of 50 μM, and with IC₅₀ values of 12.6 ± 0.2 μM–27.6 ± 1.1 μM. The most effective compounds in terms of efficacy and potency were 3b, 3h, 3j, and 3m. Among the new trifluoromethylated flavonoid-based isoxazoles, the compound 3b was the most effective inhibitor of α-amylase activity (PI = 94.7 ± 1.2% at 50 μM), with a potency (IC₅₀ = 12.6 ± 0.2 μM) similar to that of the positive control acarbose (IC₅₀ = 12.4 ± 0.1 μM). The study of the structure–activity relationship based on the molecular docking analysis showed a low binding energy, a correct mode of interaction in the active pocket of the target enzyme, and an ability to interact with the key residues of glycosidic cleavage (GLU-230 and ASP-206), explaining the inhibitory effects of α-amylase established by several derivatives.