RESUMO
Tyramine (TRM) is a biogenic catecholamine neurotransmitter, which can trigger migraines and hypertension. TRM accumulated in foods is reduced and detected using additive cyclodextrins (CDs) while their association characteristics remain unclear. Here, single-crystal X-ray diffraction and density functional theory (DFT) calculation have been performed, demonstrating the elusive pseudopolymorphs in ß-CD inclusion complexes with TRM base/HCl, ß-CD·0.5TRM·7.6H2O (1) and ß-CD·TRM HCl·4H2O (2) and the rare α-CD·0.5(TRM HCl)·10H2O (3) exclusion complex. Both 1 and 2 share the common inclusion mode with similar TRM structures in the round and elliptical ß-CD cavities, belong to the monoclinic space group P21, and have similar herringbone packing structures. Furthermore, 3 differs from 2, as the smaller twofold symmetry-related, round α-CD prefers an exclusion complex with the twofold disordered TRM-H+ sites. In the orthorhombic P21212 lattice, α-CDs are packed in a channel-type structure, where the column-like cavity is occupied by disordered water sites. DFT results indicate that ß-CD remains elliptical to suitably accommodate TRM, yielding an energetically favorable inclusion complex, which is significantly contributed by the ß-CD deformation, and the inclusion complex of α-CD with the TRM aminoethyl side chain is also energetically favorable compared to the exclusion mode. This study suggests the CD implications for food safety and drug/bioactive formulation and delivery.
Assuntos
Tiramina , Tiramina/química , beta-Ciclodextrinas/química , Modelos Moleculares , Ciclodextrinas/química , alfa-Ciclodextrinas/química , Teoria da Densidade Funcional , Cristalografia por Raios X , Difração de Raios XRESUMO
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.
Assuntos
Ciclodextrinas , beta-Ciclodextrinas , Escitalopram , Citalopram , beta-Ciclodextrinas/química , Cristalografia por Raios X , Ciclodextrinas/químicaRESUMO
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.
Assuntos
alfa-Glucosidases , Estrutura Molecular , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , alfa-Glucosidases/metabolismo , Teoria da Densidade FuncionalRESUMO
Diorygma sp. is a native crustose-lichen in Vietnam. A mycobiont of this lichen was isolated, then cultivated. The present study described the isolation and structural elucidation of two new guaiane-type sesquiterpenes, namely diorygmones A-B. Their absolute chemical structures were elucidated by extensive 1D and 2D NMR analysis, high-resolution mass spectroscopy, electronic circular dichroism (ECD), and comparisons with the literatures. Compounds 1 and 2 were evaluated for cytotoxic activity against HepG2 cell line.
RESUMO
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.
Assuntos
Ciclodextrinas , Florizina , Polifenóis , Cristalografia por Raios XRESUMO
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.
Assuntos
Lignanas , Lignanas/química , alfa-Glucosidases/metabolismo , Éter , Radicais Livres , Etil-Éteres , Éteres/farmacologia , Estrutura MolecularRESUMO
Highly anharmonic thermal vibrations may serve as a source of structural instabilities resulting in phase transitions, chemical reactions and even the mechanical disintegration of a material. Ab initio calculations model thermal motion within a harmonic or sometimes quasi-harmonic approximation and must be complimented by experimental data on temperature-dependent vibrational frequencies. Here multi-temperature atomic displacement parameters (ADPs), derived from a single-crystal synchrotron diffraction experiment, are used to characterize low-frequency lattice vibrations in the α-FOX-7 layered structure. It is shown that despite the limited quality of the data, the extracted frequencies are reasonably close to those derived from inelastic scattering, Raman measurements and density functional theory (DFT) calculations. Vibrational anharmonicity is parameterized by the Grüneisen parameters, which are found to be very different for in-layer and out-of-layer vibrations.
RESUMO
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.
Assuntos
Myristicaceae , Plantaginaceae , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Cinética , Estrutura Molecular , alfa-Glucosidases/metabolismoRESUMO
Eight undescribed cassane diterpenes, pterolobirins C-J, together with two known analogs, were isolated from the roots of Pterolobium macropterum. Their structures were characterized by extensive spectroscopic techniques including NMR, MS, ECD and X-ray crystallographic spectroscopy. The absolute configuration of pterolobirin J was confirmed by single-crystal X-ray diffraction data. The compounds were screened for their anti-inflammatory activity on the lipopolysaccharide (LPS) induced nitric oxide (NO) production in J774. A1 macrophage cells. Pterolobirin E and sucutinirane C displayed good NO inhibition with IC50 values of 24.44 ± 1.34 and 19.16 ± 1.22 µM, respectively.
Assuntos
Caesalpinia , Diterpenos , Anti-Inflamatórios/farmacologia , Caesalpinia/química , Diterpenos/química , Diterpenos/farmacologia , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Óxido NítricoRESUMO
Depression, a global mental health problem, is prevalent during the coronavirus disease 2019 (COVID-19) pandemic and can be efficiently treated by selective serotonin reuptake inhibitors (SSRIs). Our study series aims at forwarding insights on the ß-cyclodextrin (ß-CD)-SSRI inclusion complexes by X-ray crystallography combined with density functional theory (DFT) calculation. Here, we report a new crystal form (II) of the 1:1 ß-CD-paroxetine (PXT) complex, which is inspired by the reported 2:1 ß-CD-PXT complex (crystal form I), reflecting an elusive phenomenon of the polymorphism in CD inclusion complexes. The ß-CD-PXT polymorphism stems from the PXT conformational flexibility, which is defined by torsion angles κ, ε around the -CH2-O- group bridging the A- and C-D-rings, of which those of PXT in I and II are totally different. While PXT (II) in an open V-shaped conformation that has the B-ring shallowly inserted in the ß-CD cavity, PXT (I) in a closed U-shaped structure is mostly entirely embedded in the ß-CD dimeric cavity, of which the A-ring is deeply inserted in the main ß-CD cavity. However, PXT molecules in both crystal forms are similarly maintained in the CD cavity via host-guest N-H···O5/O6 H-bonds and C/O-H···π(B/C) interactions and ß-CDs have similar 3D arrangements, channel (II) vs. screw-channel (I). Further theoretical explorations on the ß-CD-PXT thermodynamic stabilities and the PXT conformational stabilities based on their potential energy surfaces (PESs) have been completed by DFT calculations. The 2:1 ß-CD-PXT complex with the greater presence of dispersion interactions is more energetically favorable than the unimolar complex. Conversely, whereas free PXT, PXT (II) and PXT in complex with serotonin transporter are more energetically stable, PXT (I) is least stable and stabilized in the ß-CD cavity. As SSRIs could lessen the COVID-19 severity, the CD inclusion complexation not only helps to improve the drug bioavailability, but also promotes the use of antidepressants and COVID-19 medicines concurrently.
RESUMO
Depression-the global crisis hastened by the coronavirus outbreak, can be efficaciously treated by the selective serotonin reuptake inhibitors (SSRIs). Cyclodextrin (CD) inclusion complexation is a method of choice for reducing side effects and improving bioavailability of drugs. Here, we investigate in-depth the ß-CD encapsulation of sertraline (STL) HCl (1) and fluoxetine (FXT) HCl (2) by single-crystal X-ray diffraction and DFT complete-geometry optimization, in comparison to the reported complex of paroxetine (PXT) base. X-ray analysis unveiled the 2:2 ß-CD-STL/FXT complexes with two drug molecules inserting their halogen-containing aromatic ring in the ß-CD dimeric cavity, which are stabilized by the interplay of intermolecular O2-Hâ¯N1-Hâ¯O3 H-bonds, C3/C5-Hâ¯π and halogenâ¯halogen interactions. Similarly, the 1:1 ß-CD-tricyclic-antidepressant (TCA) complexes have an exclusive inclusion mode of the aromatic ring, which is maintained by C3/C5-Hâ¯π interactions. By contrast, the 2:1 ß-CD-PXT complex has a total inclusion that is stabilized by host-guest O6-Hâ¯N1-Hâ¯O5 H-bonds and C3-Hâ¯π interactions. The inherent stabilization energies of 1 and 2 evaluated using DFT calculation suggested that the improved thermodynamic stabilities via CD encapsulation facilitates the reduction of drug side effects. Moreover, the SSRI conformational flexibilities are thoroughly discussed for understanding of their pharmacoactivity.
Assuntos
Inibidores Seletivos de Recaptação de Serotonina , beta-Ciclodextrinas , Cristalografia por Raios X , Teoria da Densidade Funcional , Difração de Raios XRESUMO
Depression, a global mental illness, is worsened due to the coronavirus disease 2019 (COVID-2019) pandemic. Tricyclic antidepressants (TCAs) are efficacious for the treatment of depression, even though they have more side effects. Cyclodextrins (CDs) are powerful encapsulating agents for improving molecular stability, water solubility, and lessening the undesired effects of drugs. Because the atomic-level understanding of the ß-CD-TCA inclusion complexes remains elusive, we carried out a comprehensive structural study via single-crystal X-ray diffraction and density functional theory (DFT) full-geometry optimization. Here, we focus on two complexes lining on the opposite side of the ß-CD-TCA stability spectrum based on binding constants (Kas) in solution, ß-CD-protriptyline (PRT) 1-most stable and ß-CD-maprotiline (MPL) 2-least stable. X-ray crystallography unveiled that in the ß-CD cavity, the PRT B-ring and MPL A-ring are aligned at a nearly perfect right angle against the O4 plane and primarily maintained in position by intermolecular C-H···π interactions. The increased rigidity of the tricyclic cores is arising from the PRT -CH=CH- bridge widens, and the MPL -CH2-CH2- flexure narrows the butterfly angles, facilitating the deepest and shallower insertions of PRT B-ring (1) and MPL A-ring (2) in the distorted round ß-CD cavity for better complexation. This is indicated by the DFT-derived complex stabilization energies (ΔEstbs), although the complex stability orders based on Kas and ΔEstbs are different. The dispersion and the basis set superposition error (BSSE) corrections were considered to improve the DFT results. Plus, the distinctive 3D arrangements of 1 and 2 are discussed. This work provides the first crystallographic evidence of PRT and MPL stabilized in the ß-CD cavity, suggesting the potential application of CDs for efficient drug delivery.
RESUMO
One new picrotoxane sesquiterpene (1) and one new α-pyrone derivative (4), together with nine known compounds, were isolated from the aerial parts of Dendrobium signatum. The structures of the new compounds were elucidated based on the interpretation of 1D and 2D NMR, HRESIMS and electronic circular dichroism (ECD) data. The absolute configuration of 1 was confirmed by single-crystal X-ray diffraction data. The new α-pyrone 4 exhibited promising ABTS scavenging activity with IC50 value of 0.7 µM.
Assuntos
Dendrobium , Sesquiterpenos , Radicais Livres , Estrutura Molecular , PironasRESUMO
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 OHâ â â 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 OHâ¯O H-bonds. The intermolecular OHâ â â 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.
Assuntos
Antioxidantes/química , Benzaldeídos/química , Catecóis/química , Hidroxibenzoatos/química , beta-Ciclodextrinas/química , Antioxidantes/administração & dosagem , Benzaldeídos/administração & dosagem , Catecóis/administração & dosagem , Cristalografia por Raios X , Sistemas de Liberação de Medicamentos/métodos , Ligação de Hidrogênio , Hidroxibenzoatos/administração & dosagem , Termodinâmica , beta-Ciclodextrinas/administração & dosagemRESUMO
A new rearranged clerodane-type diterpene (1), tinobaenzigeride, and a new rearranged clerodane glucoside (2) were isolated from the stems of Tinospora baenzigeri, along with four known compounds (3â6). Their structures were elucidated by spectroscopic data analysis. In addition, the structure and configuration of 1 was confirmed by single-crystal X-ray diffraction analysis. Compound 1 are a rare example of rearranged clerodanes, since it contains a fully oxygenated tetrahydrofuran moiety. The isolated compounds were evaluated for their cytotoxicity against Hep-G2 and MCF-7 cancer cells, none of them did show any significant activity at 25 µM.
Assuntos
Diterpenos Clerodânicos/química , Tinospora/química , Humanos , Estrutura Molecular , TailândiaRESUMO
Depression is a global threat. Tricyclic antidepressants (TCAs) are still efficacious in treating depression, albeit with more side effects. Cyclodextrins (CDs) with a suitable nanocavity are potential drug carriers and can enhance the drug bioavailability. Aiming for an atomistic understanding of the CD encapsulation facilitating the improvement of drug stability and the reduction of side effects, a comprehensive study series of the ß-CD-TCA inclusion complexes through single crystal X-ray diffraction and density functional theory (DFT) calculation was undertaken. This work reports the supramolecular complexes of ß-CD with two pivotal TCAs, clomipramine (CPM; 1) and doxepin (DXP; 2). The different inclusion topologies of the ß-CD-TCA complexes were notable. X-ray analysis revealed that, in 1, the CPM B-ring (without chloro group) was entrapped in the ß-CD cavity, whereas, in 2, the E-DXP A-ring and the Z-DXP B-ring were disordered in the cavity, yielding energetically favorable complexes primarily maintained by intermolecular C-Hâ¯π interactions, as indicated by DFT calculation. Because both wings of TCAs were similar, an alternative inclusion scenario of the A-ring was evidenced crystallographically in four other TCA complexes. The enhanced TCA thermodynamic stabilities via CD inclusion complexation helped to reduce the side effects and to increase the bioavailability. Moreover, the scrutinization of six TCAs in different lattice circumstances revealed the greater TCA structural flexibilities for their optimum pharmacological activity while binding with proteins.
RESUMO
Eight previously undescribed diterpenoids of different types were isolated from ethyl acetate extract of the aerial parts of Euphorbia antiquorum L., along with fifteen known diterpenoids. Their structures and configurations were determined by 1D and 2D NMR, MS, and electronic circular dichroism (ECD). Additionally, the absolute configuration of ent-12-oxo-2,3-secobeyer-15-en-2,3-dioic acid-3-methyl ester was confirmed through single-crystal X-ray diffraction. Efficacy of the compounds on lipopolysaccharide (LPS)-stimulated nitric oxide (NO) production in murine macrophage J774.A1 cells was evaluated. ent-15-Acetoxylabda-8(17),13E-diene-3-one, ent-15-oxolabda-8(17),13E-diene-3-one and rhizophorin B was significantly suppressed NO production with IC50 values of 11.7, 12.5 and 16.1 µM, respectively.
Assuntos
Euphorbia , Animais , Diterpenos/farmacologia , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico , Componentes Aéreos da PlantaRESUMO
Four new tetrahydroxanthone-chromanone heterodimers, usneaxanthones E-H (1-4) together with eleven known compounds (5-15) were isolated from lichen Usnea aciculifera Vain (Parmeliaceae). Their structures and absolute configurations, particularly the central and axial chiralities, were unambiguously demonstrated by a combination of spectroscopic data (1D, 2D NMR, HRESIMS), electronic circular dichroism (ECD) experiments, and single-crystal X-ray crystallographic analyses. The cytotoxicity of new compounds was evaluated on four human cancer cell lines including HCT116 colorectal cancer, MCF-7 breast cancer, A549 lung cancer, and OVCAR-3 ovarian cancer. Compounds 1-4 exhibited good cytotoxicity against all tested cancer cell lines, except ovarian cancer, with the best IC50 value of 3.37 µM. All compounds showed potent cytotoxicity against HCT116 colon cancer with IC50 value from 3.37 to 4.53 µM.
Assuntos
Antineoplásicos/farmacologia , Parmeliaceae/química , Xantonas/farmacologia , Antineoplásicos/isolamento & purificação , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Humanos , Estrutura Molecular , Vietnã , Xantonas/isolamento & purificaçãoRESUMO
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.
Assuntos
Caesalpinia/química , Diterpenos/isolamento & purificação , Oxigênio/química , Cristalografia por Raios X , Dimerização , Diterpenos/química , Estrutura Molecular , Análise Espectral/métodosRESUMO
Single-crystal X-ray diffraction and DFT calculation have been carried out for an atomic-level understanding of ß-cyclodextrin (ß-CD) inclusion complexation with 2 tricyclic antidepressants (TCAs), desipramine and imipramine. X-ray analysis discloses that the A-C-rings are buried in the ß-CD cavity and the side chain is mostly outside the cavity, nearby the O2-H/O3-H side. Hence, the inclusion structures of both complexes are stabilized by host-guest C5-Hâââπ interaction and N5'-HâââO5/O6 H-bonds of twofold-screw-symmetry-related molecules, which are similar to those of the reported complexes of nortriptyline and amitriptyline. The DFT full-geometry optimization in the gas phase reveals an alternative inclusion scenario with the TCA side chain that is embedded in the ß-CD cavity and stabilized by intermolecular O6-HâââN5' H-bond and O2-H/O3-Hâââπ interactions. The ß-CD encapsulation of the TCA side chain is more energetically stable by 10.76 and 4.70 kcal mol-1 than that of the aromatic moiety for the respective complexes of DPM and IPM, based on the relative stabilization energies (ΔΔEstb). This suggests the existence of the bimodal ß-CD-TCA inclusion complexes as spectroscopically observed in solution, thus explaining the controversy in the inclusion mode and the improvement of TCA therapeutic effect by CD encapsulation.