A New 3-Benzylphthalide from the Moss Erythrodontium julaceum.

From the moss Erythrodontium julaceum Paris growing in Vietnam, julacelide (1), a new 3-benzylphthalide, along with methyl orsellinate (2), ethyl orsellinate (3), 4-O-methylhaematommic acid (4), and zeorin (5), were isolated and structurally elucidated. Their chemical structures were elucidated through extensive 1D and 2D NMR analysis and high-resolution mass spectroscopy as well as through comparisons to the existing literature. Compound 4-O-methylhaematommic acid was a new natural product. The absolute configuration of julacelide was defined using time-dependent density functional theory (TDDFT) calculations. Julacelide was evaluated for α-glucosidase inhibition.

α-Glucosidase Inhibitors from the Stems of Knema globularia.

Six new compounds, globunones A-F (1-6), and two new flavonoids (7 and 8) together with nine known compounds (9-17) were isolated from the stems of Knema globularia. The chemical structures of 1-8 were elucidated by an analysis of their NMR and high-resolution electrospray ionization mass spectrometry data as well as by comparison with literature values. The absolute configurations were determined using time-dependent density functional theory electronic circular dichroism (TD-DFT-ECD). Globunones A-E (1-5) represent the initial combined structures of a flavan-3-ol core and a 1,4-benzoquinone core. Globunone F (6) is the first flavanone-type compound bearing a 2-(2,4-dihydroxyphenyl)-2-oxoethyl group found to date in Nature. Compounds 1-3 and 6-17 were tested for their yeast α-glucosidase inhibitory activity. All compounds tested (except for 13 and 14) showed potent inhibition toward α-glucosidase with IC50 values in the range 0.4-26.6 µM. Calodenin A (15) was the most active compound with an IC50 value of 0.4 µM (the positive control, acarbose, IC50 93.6 µM). A kinetic analysis of 15 revealed that it is a noncompetitive inhibitor with a Ki value of 3.4 µM.

Thioether and Ether Furofuran Lignans: Semisynthesis, Reaction Mechanism, and Inhibitory Effect against α-Glucosidase and Free Radicals.

The transformation of sesame lignans is interesting because the derived products possess enhanced bioactivity and a wide range of potential applications. In this study, the semisynthesis of 28 furofuran lignans using samin (5) as the starting material is described. Our methodology involved the protonation of samin (5) to generate an oxocarbenium ion followed by the attack from two different nucleophiles, namely, thiols (RSH) and alcohols (ROH). The highly diastereoselective thioether and ether furofuran lignans were obtained, and their configurations were confirmed by 2D NMR and X-ray crystallography. The mechanism underlying the reaction was studied by monitoring 1H NMR and computational calculations, that is, the diastereomeric α- and ß-products were equally formed through the SN1-like mechanism, while the ß-product was gradually transformed via an SN2-like mechanism to the α-congener in the late step. Upon evaluation of the inhibitory effect of the synthesized lignans against α-glucosidases and free radicals, the lignans 7f and 7o of the phenolic hydroxyl group were the most potent inhibitors. Additionally, the mechanisms underlying the α-glucosidase inhibition of 7f and 7o were verified to be of a mixed manner and noncompetitive inhibition, respectively. The results indicated that both 7f and 7o possessed promising antidiabetic activity, while simultaneously inhibiting α-glucosidases and free radicals.

ß-Cyclodextrin Inclusion Complexes with Catechol-Containing Antioxidants Protocatechuic Aldehyde and Protocatechuic Acid-An Atomistic Perspective on Structural and Thermodynamic Stabilities.

Protocatechuic aldehyde (PCAL) and protocatechuic acid (PCAC) are catechol derivatives and have broad therapeutic effects associated with their antiradical activity. Their pharmacological and physicochemical properties have been improved via the cyclodextrin (CD) encapsulation. Because the characteristics of ß-CD inclusion complexes with PCAL (1) and PCAC (2) are still equivocal, we get to the bottom of the inclusion complexation by an integrated study of single-crystal X-ray diffraction and DFT full-geometry optimization. X-ray analysis unveiled that PCAL and PCAC are nearly totally shielded in the ß-CD wall. Their aromatic rings are vertically aligned in the ß-CD cavity such that the functional groups on the opposite side of the ring (3,4-di(OH) and 1-CHO/1-COOH groups) are placed nearby the O6-H and O2-H/O3-H rims, respectively. The preferred inclusion modes in 1 and 2 help to establish crystal contacts of OH⋅⋅⋅O H-bonds with the adjacent ß-CD OH groups and water molecules. By contrast, the DFT-optimized structures of both complexes in the gas phase are thermodynamically stable via the four newly formed host-guest OH⋯O H-bonds. The intermolecular OH⋅⋅⋅O H-bonds between PCAL/PCAC 3,4-di(OH) and ß-CD O6-H groups, and the shielding of OH groups in the ß-CD wall help to stabilize these antioxidants in the ß-CD cavity, as observed in our earlier studies. Moreover, PCAL and PCAC in distinct lattice environments are compared for insights into their structural flexibility.

Pterolobirins A and B, Oxygen-Bridged Cassane Diterpenoid Dimers from the Fruits of Pterolobium macropterum.

Two dimeric cassane diterpenoids with an unprecedented 6/6/6/6/6/5/6/6/6 nonacyclic framework, pterolobirins A and B (1 and 2), were isolated from the fruits of Pterolobium macropterum. Their structures were assigned by interpreting the spectroscopic data. The absolute configuration of 1 was unequivocally confirmed by single-crystal X-ray diffraction data. A putative biosynthetic pathway is proposed based on a regular intermolecular Diels-Alder reaction and an intramolecular nucleophilic addition.

Picrorhizones A-H, Polyprenylated Benzoylphloroglucinols from the Stem Bark of Garcinia picrorhiza.

Eight new polyprenylated benzoylphloroglucinol derivatives (1-8) and four known analogues (9-12) were isolated from the stem bark of Garcinia picrorhiza. Their structures were determined by spectroscopic data analysis (1D and 2D NMR and HRESIMS), and the absolute configurations were established by single-crystal X-ray diffraction combined with experimental and calculated ECD data. The new metabolites represent rare examples of benzoylphloroglucinols bearing a cyclobutyl-containing side chain. The isolated compounds were evaluated for their cytotoxic properties against five types of human cancer cells (KB, HeLa S3, MCF-7, Hep G2, and HT-29 cells) and their inhibitory activities against COX-1 and COX-2 enzymes. The cytotoxicity results showed that compound 6 was active against KB, HeLa S3, MCF-7, and Hep G2 cancer cells, with IC50 values ranging from 5.9 to 9.4 µM. Among the compounds tested for cyclooxygenase inhibition, compound 8 possessed the highest inhibitory effect toward COX-1 (35.2 ± 9.6% inhibition at 20 µM).

Tsavoenones A-C: unprecedented polyketides with a 1,7-dioxadispiro[4.0.4.4]tetradecane core from the lichen Parmotrema tsavoense.

New racemic dispiranic polyketides, tsavoenones A (1), B (2) and C (3), having a novel 1,7-dioxadispiro[4.0.4.4]tetradecane scaffold were isolated from the foliose lichen Parmotrema tsavoense. These compounds were structurally elucidated by extensive NMR analyses, comparison between experimental and theoretical 13C NMR data and X-ray crystallography. A putative biosynthetic scenario for the formation of 1-3 from parmosidone D, a meta-depsidone previously isolated from the same lichen material, was proposed. Tested for its cytotoxicity, 1 displayed a moderate activity against human myelogenous leukemia K562 cell line with an IC50 value of 66 µg mL-1.

Biotransformation of ß-Mangostin by an Endophytic Fungus of Garcinia mangostana to Furnish Xanthenes with an Unprecedented Heterocyclic Skeleton.

Biotransformation of ß-mangostin (1) by the endophytic fungus Xylaria feejeensis GM06 afforded hexacyclic ring-fused xanthenes with an unprecedented hexacyclic heterocylic skeleton. ß-Mangostin (1) was transformed to two diastereomeric pairs of enantiomers, mangostafeejin A [(-)-2a/(+)-2b)] and mangostafeejin B [(-)-3a/(+)-3b)]. The chemical structures of the transformation products were elucidated by analysis of NMR and MS data, and the structure of mangostafeejin A [(-)-2a/(+)-2b)] was confirmed by single-crystal X-ray diffraction analysis. The absolute configurations of 3a and 3b were established on the basis of calculated and measured ECD data using the ECD spectra of 2a and 2b as models. The fungal biotransformation described herein provides an effective method to convert an abundant achiral plant natural product scaffold into new chiral heterocyclic scaffolds representing expanded chemical diversity for biological activity screening.

Sulfonic Acid-Containing Flavonoids from the Roots of Phyllanthus acidus.

Six new sulfonic acid-containing flavonoids, acidoflavanone (1), acidoauronol (2), 5- O-methylacidoauronol (3), acidoaurone (4), acidoisoflavone (5), and acidoflavonol (6), were isolated from the EtOH extract of the roots of Phyllanthus acidus. Their structures were unambiguously established by interpretation of their HRESIMS and 1D and 2D NMR data, single-crystal X-ray diffraction analysis, and comparison to the literature data. These new structures represent the first examples of sulfonic acid-containing flavanones, auronols, aurones, and isoflavones.

Cytotoxic Flavones from the Stem Bark of Bougainvillea spectabilis Willd.

Five new flavones possessing a fully substituted A-ring with C-6 and C-8 methyl groups, bougainvinones I - M (1: -5: ), along with three known congeners, 2'-hydroxydemethoxymatteucinol (6: ), 5,7,3',4'-tetrahydroxy-3-methoxy-6,8-dimethylflavone (7: ) and 5,7,4'-trihydroxy-3-methoxy-6,8-dimethylflavone (8: ), were isolated from the EtOAc extract of the stem bark of Bougainvillea spectabilis. Their structures were established by means of spectroscopic data (ultraviolet, infrared, high-resolution electrospray ionization mass spectrometry, and one-dimensional and two-dimensional nuclear magnetic resonance) and single-crystal X-ray crystallographic analysis. The in vitro cytotoxicity of all isolated compounds against five cancer cell lines (KB, HeLa S-3, MCF-7, HT-29, and HepG2) was evaluated. Compound 5: showed promising cytotoxic activity against the KB and HeLa S-3 cell lines, with IC50 values of 7.44 and 6.68 µM. The other compounds exhibited moderate cytotoxicity against the KB cell line.

Identification of highly potent α-glucosidase inhibitory and antioxidant constituents from Zizyphus rugosa bark: enzyme kinetic and molecular docking studies with active metabolites.

CONTEXT: Previous studies have shown that extracts of Zizyphus rugosa Lam. (Rhamnaceae) bark contained phytoconstituents with antidiabetic potential to lower blood glucose levels in diabetic rats. However, there has been no report on the active compounds in this plant as potential antidiabetic inhibitors. OBJECTIVE: We evaluated the α-glucosidase inhibitory and antioxidant activities of Z. rugosa extract. Moreover, the active phytochemical constituents were isolated and characterized. MATERIALS AND METHODS: The α-glucosidase inhibition of crude ethanol extract obtained from the bark of Z. rugosa was assayed as well as the antioxidant activity. Active compounds (1-6) were isolated, the structures were determined, and derivatives (2a-2 l) were prepared. All compounds were tested for their α-glucosidase inhibitory (yeast and rat intestine) and antioxidant (DPPH) activities. RESULTS: The active α-glucosidase inhibitors (1-6) were isolated from Z. rugosa bark and 12 derivatives (2a-2 l) were prepared. Compound 2 showed the most powerful yeast α-glucosidase inhibitory activity (IC50 16.3 µM), while compounds 3 and 4 display only weak inhibition toward rat intestinal α-glucosidase. Moreover, compound 6 showed the most potent antioxidant activity (IC50 42.8 µM). The molecular docking results highlighted the role of the carboxyl moiety of 2 for yeast α-glucosidase inhibition through H-bonding. DISCUSSION AND CONCLUSIONS: These results suggest the potential of Z. rugosa bark for future application in the treatment of diabetes and active compounds 1 and 2 have emerged as promising molecules for therapy.

Fluorescent Chemosensors for Selective and Sensitive Detection of Phosmet/Chlorpyrifos with Octahedral Ni(2+) Complexes.

The hexadentate ligands H2L1-L3 with mixed S, N, O donor sites and possessing substituents having either "no" or electron-releasing/withdrawing nature at terminal ends are synthesized. The ligands H2L1-L3 were tested for binding with library of metal ions, wherein maximum efficiency was observed with Ni(2+), and it motivated us to prepare the Ni(2+) complexes. The ligand H2L1 underwent deprotonation and formed binuclear complex when interacted with Ni(2+) as evident from its crystal structure. The H2L2 and H2L3 having electron-withdrawing/electron releasing groups, respectively, were also deprotonated; however, they afforded mononuclear complexes with Ni(2+) ion. This signifies the importance of steric parameters instead of electronic factors in these particular cases. Impressed by differential behavior of complexes of H2L1 and H2L2/H2L3 with Ni(2+) and their photophysical and electrochemical properties, all the metal complexes were studied for their chemosensing ability. Nowadays with increased use of organophosphate, there is alarming increase of these agents in the environment, and thus we require efficient technique to estimate the level of these agents with high sensitivity and selectivity in aqueous medium. The Ni(2+) complexes with hydrophobic nature were suspended into aqueous medium for testing them as sensor for organophosphate. The (L1)2.(Ni(2+))2 could sense phosmet with detection limit of 44 nM, whereas L2.Ni(2+) and L3.Ni(2+) exhibited the detection limits of 62 and 71 nM, respectively, for chlorpyrifos.

Bougainvinones A-H, Peltogynoids from the Stem Bark of Purple Bougainvillea spectabilis and Their Cytotoxic Activity.

Eight new peltogynoids, named bougainvinones A-H (1-8), were obtained from the stem bark of Bougainvillea spectabilis. Their structures were elucidated by means of physical data (1D and 2D NMR, HRESIMS) and single-crystal X-ray crystallographic analyses. The peltogynoids, a rare type of modified flavonoids, are reported for the first time from this species of the genus Bougainvillea. All isolated compounds were evaluated for their cytotoxic effects against five cancer cell lines including KB, Hela S-3, HT-29, MCF-7, and HepG2. Among them, compound 7 showed cytotoxicity against five cancer cell lines with IC50 values in the 7.4-9.7 µM range, and compounds 2 and 3 exhibited cytotoxicity against the KB cell line with IC50 values of 6.6 and 9.0 µM.

Water-Assisted Nitrile Oxide Cycloadditions: Synthesis of Isoxazoles and Stereoselective Syntheses of Isoxazolines and 1,2,4-Oxadiazoles.

Conventional methods generate nitrile oxides from oxime halides in organic solvents under basic conditions. However, the present work revealed that water-assisted generation of nitrile oxides proceeds under mild acidic conditions (pH 4-5). Cycloadditions of nitrile oxides with alkynes and alkenes easily occurred in water without using catalysts, thus yielding isoxazoles and isoxazolines, respectively, with excellent stereoselectivity toward five- and six-membered cyclic alkenes. A double stereoselective cycloaddition of two units of a nitrile oxide with cyclohexene was also achieved, thus yielding 1,2,4-oxadiazole derivatives having a unique hybrid isoxazoline-oxadiazole skeleton. Enantiomerically pure isoxazolines were prepared from monoterpenes with a ring strain. In one case, the isoxazoline with a butterfly-like structure was simply prepared, and it might be used as a ligand in asymmetric catalysis.

Drimane Sesquiterpene-Conjugated Amino Acids from a Marine Isolate of the Fungus Talaromyces minioluteus (Penicillium Minioluteum).

Four new sesquiterpene lactones (3, 4, 6 and 7) and three known compounds, purpuride (1), berkedrimane B (2) and purpuride B (5), were isolated from the marine fungus, Talaromyces minioluteus (Penicillium minioluteum). New compounds were drimane sesquiterpenes conjugated with N-acetyl-l-valine, and their structures were elucidated by analysis of spectroscopic data, as well as by single crystal X-ray analysis. The isolated compounds could not inhibit the apoptosis-regulating enzyme, caspase-3, while three of the compounds (2, 3 and 7) exhibited weak cytotoxic activity.

Dynamics and thermodynamics of crystalline polymorphs. 3. γ-Glycine, analysis of variable-temperature atomic displacement parameters, and comparison of polymorph stabilities.

In a series of systematic studies, we have investigated the molecular motion in crystals of the glycine polymorphs and determined their thermodynamic functions from an analysis of multitemperature atomic displacement parameters (ADPs) combined with ONIOM calculation on 15-molecule clusters. The studies are aimed at providing insight into the factors governing the relative stabilities of the α-, ß-, and γ-polymorphs. This Article, the last in the series, focuses on the most stable polymorph, γ-glycine. Multitemperature diffraction data of the γ-glycine polymorph have been collected to 0.5 Å resolution between 10 and 300 K at two synchrotron beamlines, KEK Photon Factory and ID11 of the ESRF. The ADPs of γ-glycine from these sources differ significantly, as previously observed also for the other two polymorphs. A simple model of rigid body motion explains the ADPs from KEK and their temperature dependence. It provides lattice vibration frequencies that are in line with those from Raman spectroscopy. Together with the internal vibration frequencies from an ONIOM calculation, the thermodynamic functions are estimated using the Einstein, Debye, and Nernst-Lindemann models of heat capacity. The relative stabilities of the three polymorphs of glycine are discussed on the basis of the contributions to their free energies as obtained in this work and from various experimental and theoretical studies. The comparison shows that the free-energy differences are determined primarily by differences in lattice and zero-point vibrational energies.

Supramolecular assemblies of citalopram and escitalopram in ß-cyclodextrin dimeric cavity: Crystallographic and theoretical insights.

Cyclodextrin (CD) encapsulation improves physicochemical and pharmacological properties of selective serotonin reuptake inhibitors (SSRIs), which are efficacious in treating depression, a global mental health problem. Here, we scrutinize ß-CD inclusion complexes with racemate citalopram (rac-CTP; 1) and escitalopram ((S)-CTP; 2) by combined single-crystal X-ray diffraction and DFT full-geometry optimization. X-ray analysis unveiled that the 2:2 inclusion complexes of 1 and 2 with similar inclusion modes and topologies are stabilized by various intermolecular interactions of host-guest CH···π, host-host OH···O H-bonds, and guest-guest F···F in the tail-to-tail dimeric asymmetric unit. In the crystals, these dimers are stacked on top of each other, yielding similar channel structures of distinct crystal symmetries, triclinic, P1 (1) and monoclinic, P21 (2), which are further maintained by guest-guest π···π and CN···π interactions. The thermodynamic stabilities evaluated by DFT calculation indicate the vital role of weak intermolecular interactions in the formation and stabilization of the ß-CD monomeric and dimeric inclusion complexes. This study provides crystallographic and theoretical evidence for the improved stability and the masked bitterness of CTP through ß-CD encapsulation as patented previously and suggests the pharmaceutical implications in the drug delivery and enantioseparation.

Fluorescent organic nanoparticles of Biginelli-based molecules: recognition of Hg2+ and Cl- in an aqueous medium.

Biginelli-based molecules (1-3) have been synthesized and developed as a new class of fluorescent organic nanoparticle-based chemosensors. Chemosensor 2 has shown excellent selectivity and sensitivity for detection of Hg(2+) in an aqueous medium. It can detect Hg(2+) up to 1 nM, and the resultant 2Hg(2+) complex can detect Cl(-) ions (micromolar level) in an aqueous medium.

Dynamics and thermodynamics of crystalline polymorphs. 2. ß-Glycine, analysis of variable-temperature atomic displacement parameters.

The molecular dynamics in the crystal and the thermodynamic functions of the ß-polymorph of glycine have been determined from a combination of molecular translation-libration frequencies reflecting the temperature dependence of atomic displacement parameters (ADPs), with frequencies derived from ONIOM(DFT:PM3) calculations on a 15-molecule ß-glycine cluster. ADPs have been obtained from variable-temperature diffraction data to 0.5 Å resolution collected with X-ray synchrotron (10-300 K) and sealed tube radiation (50-298 K). At the higher temperatures, the ADPs of ß-glycine from synchrotron are larger than those from sealed tube probably due to different experimental conditions. The lattice vibration frequencies from normal-mode analysis of ADPs and the internal vibration frequencies from ONIOM(B3LYP/6-311+G(2d,p):PM3) calculations agree with those from spectroscopy. Estimation of thermodynamic functions using the vibrational frequencies, the Einstein and Debye models of heat capacity, and the room-temperature compressibility provides C(p), H(vib), and S(vib) that agree with those from calorimetry. The ß-phase with higher H and G is found to be less stable than the α-phase in the temperature range of the experiment.

How cyclodextrin encapsulation improves molecular stability of apple polyphenols phloretin, phlorizin, and ferulic acid: Atomistic insights through structural chemistry.

Phloretin (PRT), phlorizin (PRZ), and ferulic acid (FEA) prevalent in apples are unstable and less soluble in water, which can be improved by cyclodextrin (CD) encapsulation. This study aimed to provide atomistic insights of ß-CD-PRT (1), ß-CD-PRZ (2), and α-CD-FEA (3) complexes. Single-crystal X-ray diffraction (XRD) revealed that one PRZ (2) and one FEA (3) insert the aromatic B-ring and C=C-C=O(O) group respectively into the ß-CD (2) and α-CD (3) cavities, whereas a half-occupied PRT (1) inserts the B-ring across the ß-CD cavity. The induced-fit process yielded thermodynamically stable complexes 2 > 1 > 3, in agreement with the density functional theory (DFT)-optimized structures with the corresponding number of intermolecular OH···O H-bonds (7 > 3 > 1). Perpendicular conformations of the pharmaceutically active forms of PRT (1) and PRZ (2) are first observed crystallographically. This study confirmed the potential applications of CDs as molecular stabilizers and aqueous solubilizers for the improved bioavailability and efficient delivery of food bioactive compounds.