International Journal of Molecular Sciences

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Open AccessEditorial

Host–Guest Complexes

by Juan C. Mejuto and Jesus Simal-Gandara

Int. J. Mol. Sci. 2022, 23(24), 15730; https://doi.org/10.3390/ijms232415730 - 12 Dec 2022

Cited by 2 | Viewed by 2065

Abstract

Host–guest complexes, also known as inclusion complexes, are supramolecular structures [...] Full article

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17 pages, 2540 KiB

Open AccessArticle

Capsaicin-Cyclodextrin Complex Enhances Mepivacaine Targeting and Improves Local Anesthesia in Inflamed Tissues

by Verônica Muniz Couto, Laura de Oliveira-Nascimento, Luiz Fernando Cabeça, Danilo Costa Geraldes, Juliana Souza Ribeiro Costa, Karin A. Riske, Michelle Franz-Montan, Fabiano Yokaychiya, Margareth K. K. Dias Franco and Eneida de Paula

Int. J. Mol. Sci. 2020, 21(16), 5741; https://doi.org/10.3390/ijms21165741 - 10 Aug 2020

Cited by 14 | Viewed by 3718

Abstract

Acidic environments, such as in inflamed tissues, favor the charged form of local anesthetics (LA). Hence, these drugs show less cell permeation and diminished potency. Since the analgesic capsaicin (CAP) triggers opening of the TRPV1 receptor pore, its combination with LAs could result [...] Read more.

Acidic environments, such as in inflamed tissues, favor the charged form of local anesthetics (LA). Hence, these drugs show less cell permeation and diminished potency. Since the analgesic capsaicin (CAP) triggers opening of the TRPV1 receptor pore, its combination with LAs could result in better uptake and improved anesthesia. We tested the above hypothesis and report here for the first time the analgesia effect of a two-drug combination (LA and CAP) on an inflamed tissue. First, CAP solubility increased up to 20 times with hydroxypropyl-beta-cyclodextrin (HP-β-CD), as shown by the phase solubility study. The resulting complex (HP-β-CD-CAP) showed 1:1 stoichiometry and high association constant, according to phase-solubility diagrams and isothermal titration calorimetry data. The inclusion complex formation was also confirmed and characterized by differential scanning calorimetry (DSC), X-ray diffraction, and ¹H-NMR. The freeze-dried complex showed physicochemical stability for at least 12 months. To test in vivo performance, we used a pain model based on mouse paw edema. Results showed that 2% mepivacaine injection failed to anesthetize mice inflamed paw, but its combination with complexed CAP resulted in pain control up to 45 min. These promising results encourages deeper research of CAP as an adjuvant for anesthesia in inflamed tissues and cyclodextrin as a solubilizing agent for targeting molecules in drug delivery. Full article

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18 pages, 2767 KiB

Open AccessArticle

Development and Evaluation of Antimicrobial and Modulatory Activity of Inclusion Complex of Euterpe oleracea Mart Oil and β-Cyclodextrin or HP-β-Cyclodextrin

by Thalita Sévia Soares de Almeida Magalhães, Pollyana Cristina de Oliveira Macedo, Stephany Yumi Kawashima Pacheco, Sofia Santos da Silva, Euzébio Guimarães Barbosa, Rayanne Rocha Pereira, Roseane Maria Ribeiro Costa, José Otávio Carréra Silva Junior, Marília Andreza da Silva Ferreira, José Cezário de Almeida, Pedro José Rolim Neto, Attilio Converti and Ádley Antonini Neves de Lima

Int. J. Mol. Sci. 2020, 21(3), 942; https://doi.org/10.3390/ijms21030942 - 31 Jan 2020

Cited by 33 | Viewed by 3934

Abstract

The development of inclusion complexes is used to encapsulate nonpolar compounds and improve their physicochemical characteristics. This study aims to develop complexes made up of Euterpe oleracea Mart oil (EOO) and β-cyclodextrin (β-CD) or hydroxypropyl-β-cyclodextrin (HP-β-CD) by either kneading (KND) or slurry (SL). [...] Read more.

The development of inclusion complexes is used to encapsulate nonpolar compounds and improve their physicochemical characteristics. This study aims to develop complexes made up of Euterpe oleracea Mart oil (EOO) and β-cyclodextrin (β-CD) or hydroxypropyl-β-cyclodextrin (HP-β-CD) by either kneading (KND) or slurry (SL). Complexes were analyzed by molecular modeling, Fourier-transform infrared spectroscopy, scanning electron microscopy, powder X-ray diffraction, thermogravimetry analysis and differential scanning calorimetry. The antibacterial activity was expressed as Minimum Inhibitory Concentration (MIC), and the antibiotic resistance modulatory activity as subinhibitory concentration (MIC/8) against Escherichia coli, Streptomyces aureus, Pseudomonas aeruginosa and Enterococcus faecalis. Inclusion complexes with β-CD and HP-β-CD were confirmed, and efficiency was proven by an interaction energy between oleic acid and β-CD of −41.28 ± 0.57 kJ/mol. MIC values revealed higher antibacterial activity of complexes compared to the isolated oil. The modulatory response of EOO and EOO-β-CD prepared by KND as well as of EOO-β-CD and EOO-HP-β-CD prepared by SL showed a synergistic effect with ampicillin against E. coli, whereas it was not significant with the other drugs tested, maintaining the biological response of antibiotics. The antimicrobial response exhibited by the complexes is of great significance because it subsidizes studies for the development of new pharmaceutical forms. Full article

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18 pages, 3107 KiB

Open AccessArticle

Cyclodextrin-Elicited Bryophyllum Suspension Cultured Cells: Enhancement of the Production of Bioactive Compounds

by Pascual García-Pérez, Sonia Losada-Barreiro, Pedro P. Gallego and Carlos Bravo-Díaz

Int. J. Mol. Sci. 2019, 20(20), 5180; https://doi.org/10.3390/ijms20205180 - 18 Oct 2019

Cited by 23 | Viewed by 3016

Abstract

The rates of production of secondary metabolites obtained by employing conventional plant breeding may be low for practical purposes. Thus, innovative approaches for increasing their rates of production are being developed. Here, we propose the use of elicited plant suspension cultured cells (PSCC) [...] Read more.

The rates of production of secondary metabolites obtained by employing conventional plant breeding may be low for practical purposes. Thus, innovative approaches for increasing their rates of production are being developed. Here, we propose the use of elicited plant suspension cultured cells (PSCC) with cyclodextrins (CDs) as an alternative method for the production of bioactive compounds from Bryophyllum species. For this purpose, we analyzed the effects of methyl–β–cyclodextrin and 2–hydroxypropyl–β–cyclodextrin on cell culture growth and on the intra- and extracellular production of phenols and flavonoids. Results clearly show that CDs enhance the biosynthesis of polyphenols by PSCC favoring their accumulation outside the cells. CDs shift the homeostatic equilibrium by complexing extracellular phenolics, causing stress in cells that respond by increasing the production of intracellular phenolics. We also analyzed the radical scavenging activity of the culture medium extracts against 2,2–diphenyl–1–pycrilhydrazyl (DPPH) radical, which increased with respect to the control samples (no added CDs). Our results suggest that both the increase in the production of polyphenols and their radical scavenging activity are a consequence of their inclusion in the CD cavities. Overall, based on our findings, CDs can be employed as hosts for increasing the production of polyphenols from Bryophyllum species. Full article

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16 pages, 6680 KiB

Open AccessArticle

Chiral Cocrystal Solid Solutions, Molecular Complexes, and Salts of N-Triphenylacetyl-l-Tyrosine and Diamines

by Agnieszka Czapik, Maciej Jelecki and Marcin Kwit

Int. J. Mol. Sci. 2019, 20(20), 5004; https://doi.org/10.3390/ijms20205004 - 10 Oct 2019

Cited by 9 | Viewed by 3108

Abstract

The molecular recognition process and the ability to form multicomponent supramolecular systems have been investigated for the amide of triphenylacetic acid and l-tyrosine (N-triphenylacetyl-l-tyrosine, TrCOTyr). The presence of several supramolecular synthons within the same amide molecule allows the [...] Read more.

The molecular recognition process and the ability to form multicomponent supramolecular systems have been investigated for the amide of triphenylacetic acid and l-tyrosine (N-triphenylacetyl-l-tyrosine, TrCOTyr). The presence of several supramolecular synthons within the same amide molecule allows the formation of various multicomponent crystals, where TrCOTyr serves as a chiral host. Isostructural crystals of solvates with methanol and ethanol and a series of binary crystalline molecular complexes with selected organic diamines (1,5-naphthyridine, quinoxaline, 4,4′-bipyridyl, and DABCO) were obtained. The structures of the crystals were planned based on non-covalent interactions (O–H···N or N–H⁺···O⁻ hydrogen bonds) present in a basic structural motif, which is a heterotrimeric building block consisting of two molecules of the host and one molecule of the guest. The complex of TrCOTyr with DABCO is an exception. The anionic dimers built off the TrCOTyr molecules form a supramolecular gutter, with trityl groups located on the edge and filled by DABCO cationic dimers. Whereas most of the racemic mixtures crystallize as racemic crystals or as conglomerates, the additional tests carried out for racemic N-triphenylacetyl-tyrosine (rac-TrCOTyr) showed that the compound crystallizes as a solid solution of enantiomers. Full article

(This article belongs to the Special Issue Host-Guest Complexes)

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12 pages, 3980 KiB

Open AccessArticle

A Molecular Dynamics Study of a Photodynamic Sensitizer for Cancer Cells: Inclusion Complexes of γ-Cyclodextrins with C₇₀

by Giuseppina Raffaini and Fabio Ganazzoli

Int. J. Mol. Sci. 2019, 20(19), 4831; https://doi.org/10.3390/ijms20194831 - 28 Sep 2019

Cited by 13 | Viewed by 3103

Abstract

Photodynamic therapy is an emerging treatment of tumor diseases. The complexes with γ-cyclodextrins (γ-CD) and fullerenes or their derivatives can be used as photosensitizers by direct injection into cancer cells. Using molecular mechanics and molecular dynamics methods, the stability and the geometry of [...] Read more.

Photodynamic therapy is an emerging treatment of tumor diseases. The complexes with γ-cyclodextrins (γ-CD) and fullerenes or their derivatives can be used as photosensitizers by direct injection into cancer cells. Using molecular mechanics and molecular dynamics methods, the stability and the geometry of the 2:1 complexes [(γ-CD)₂/C₇₀] are investigated analyzing the differences with the analogous C₆₀ complexes, studied in a previous theoretical work and experimentally found to be much less efficient in cancer therapy. The inclusion complex of γ-CD and C₇₀ has a 2:1 stoichiometry, the same as C₆₀, but is significantly less stable and displays an unlike arrangement. In vacuo, mimicking an apolar solvent, the complex is compact, whereas in water the two γ-CDs encapsulate C₇₀ forming a relatively stable complex by interacting through their primary rims, however exposing part of C₇₀ to the solvent. Other higher-energy complexes with the γ-CDs facing different rims can form in water, but in all cases part of the hydrophobic C₇₀ surface remains exposed to water. The stability and arrangement of these peculiar amphiphilic inclusion complexes having non-covalent interactions in water can be an important key for cancer therapy to enhance both the solubilization and the fullerene insertion into liposomes or cell membranes. Full article

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15 pages, 2727 KiB

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Nitropyridine-1-Oxides as Excellent π-Hole Donors: Interplay between σ-Hole (Halogen, Hydrogen, Triel, and Coordination Bonds) and π-Hole Interactions

by Bartomeu Galmés, Antonio Franconetti and Antonio Frontera

Int. J. Mol. Sci. 2019, 20(14), 3440; https://doi.org/10.3390/ijms20143440 - 12 Jul 2019

Cited by 20 | Viewed by 4470

Abstract

In this manuscript, we use the primary source of geometrical information, i.e., Cambridge Structural Database (CSD), combined with density functional theory (DFT) calculations (PBE0-D3/def2-TZVP level of theory) to demonstrate the relevance of π-hole interactions in para-nitro substituted pyridine-1-oxides. More importantly, we show that [...] Read more.

In this manuscript, we use the primary source of geometrical information, i.e., Cambridge Structural Database (CSD), combined with density functional theory (DFT) calculations (PBE0-D3/def2-TZVP level of theory) to demonstrate the relevance of π-hole interactions in para-nitro substituted pyridine-1-oxides. More importantly, we show that the molecular electrostatic potential (MEP) value above and below the π–hole of the nitro group is largely influenced by the participation of the N-oxide group in several interactions like hydrogen-bonding (HB) halogen-bonding (XB), triel bonding (TrB), and finally, coordination-bonding (CB) (N⁺–O⁻ coordinated to a transition metal). The CSD search discloses that p-nitro-pyridine-1-oxide derivatives have a strong propensity to participate in π-hole interactions via the nitro group and, concurrently, N-oxide group participates in a series of interactions as electron donor. Remarkably, the DFT calculations show from strong to moderate cooperativity effects between π–hole and HB/XB/TrB/CB interactions (σ-bonding). The synergistic effects between π-hole and σ-hole bonding interactions are studied in terms of cooperativity energies, using MEP surface analysis and the Bader’s quantum theory of atoms in molecules (QTAIM). Full article

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Review

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15 pages, 3430 KiB

Open AccessReview

Macrocyclic Compounds for Drug and Gene Delivery in Immune-Modulating Therapy

by Hongzhen Bai, Jianwei Wang, Zhongbao Li and Guping Tang

Int. J. Mol. Sci. 2019, 20(9), 2097; https://doi.org/10.3390/ijms20092097 - 28 Apr 2019

Cited by 39 | Viewed by 4683

Abstract

For decades, macrocyclic compounds have been widely applied in various fields owing to essential physicochemical properties such as their rigid cyclic structures, geometric dimensions (diameter and height), hydrophobic cavity, and hydrophilic interface. This review is an attempt to summarize various research accomplishments involving [...] Read more.

For decades, macrocyclic compounds have been widely applied in various fields owing to essential physicochemical properties such as their rigid cyclic structures, geometric dimensions (diameter and height), hydrophobic cavity, and hydrophilic interface. This review is an attempt to summarize various research accomplishments involving macrocyclic compounds for drug and gene delivery in immune-modulating therapies: the structures and benefits of main host molecules, their mechanisms regulating the immune system from cell uptake to activation of dendritic cells and T helper lymphocytes, as well as their potential immunotherapy for different diseases. Macrocyclic compounds including cucurbiturils (CBs), calixarenes, pillararenes, cyclodextrins (CyDs), macrocyclic peptides and metallo-supramolecular compounds, have their own unique physicochemical properties and functional derivatizations that enable to improve the biocompatibility, responsiveness to stimuli, and effectiveness of immune-modulating therapy. Based on abundant clarifications of the biological immunity mechanisms, representative constructions of macrocyclic compounds for immune therapies have been conducted for the investigation of treatment of different diseases including cancer, atherosclerosis, Niemann-Pick type C1 disease (NPC1), diabetes, and inflammations. Although there are critical challenges that remain to be conquered, we believe the future of macrocyclic compounds in the immune-modulating therapy must be bright. Full article

(This article belongs to the Special Issue Host-Guest Complexes)

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