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1.
Pharmaceutics ; 16(2)2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38399286

RESUMO

Ocular pathologies present significant challenges to achieving effective therapeutic results due to various anatomical and physiological barriers. Natural products such as flavonoids, alone or in association with allopathic drugs, present many therapeutic actions including anticancer, anti-inflammatory, and antibacterial action. However, their clinical employment is challenging for scientists due to their low water solubility. In this study, we designed a liquid formulation based on rutin/sulfobutylether-ß-cyclodextrin (RTN/SBE-ß-CD) inclusion complex for treating ocular infections. The correct stoichiometry and the accurate binding constant were determined by employing SupraFit software (2.5.120) in the UV-vis titration experiment. A deep physical-chemical characterization of the RTN/SBE-ß-CD inclusion complex was also performed; it confirmed the predominant formation of a stable complex (Kc, 9660 M-1) in a 1:1 molar ratio, with high water solubility that was 20 times (2.5 mg/mL) higher than the free molecule (0.125 mg/mL), permitting the dissolution of the solid complex within 30 min. NMR studies revealed the involvement of the bicyclic flavonoid moiety in the complexation, which was also confirmed by molecular modeling studies. In vitro, the antibacterial and antibiofilm activity of the formulation was assayed against Staphylococcus aureus and Pseudomonas aeruginosa strains. The results demonstrated a significant activity of the formulation than that of the free molecules.

2.
Pharmaceutics ; 15(9)2023 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-37765179

RESUMO

Morin (MRN) is a natural compound with antiangiogenic, antioxidant, anti-inflammatory, and anticancer activity. However, it shows a very low water solubility (28 µg/mL) that reduces its oral absorption, making bioavailability low and unpredictable. To improve MRN solubility and positively affect its biological activity, particularly its antiangiogenic activity, in this work, we prepared the inclusion complexes of MNR with sulfobutylether-ß-cyclodextrin (SBE-ß-CD) and hydroxypropyl-ß-cyclodextrin (HP-ß-CD). The inclusion complexes obtained by the freeze-drying method were extensively characterized in solution (phase-solubility studies, UV-Vis titration, and NMR spectroscopy) and in the solid state (TGA, DSC, and WAXD analysis). The complexation significantly increased the water solubility by about 100 times for MRN/HP-ß-CD and 115 times for MRN/SBE-ß-CD. Furthermore, quantitative dissolution of the complexes was observed within 60 min, whilst 1% of the free drug dissolved in the same experimental time. 1H NMR and UV-Vis titration studies demonstrated both CDs well include the benzoyl moiety of the drug. Additionally, SBE-ß-CD could interact with the cinnamoyl moiety of MRN too. The complexes are stable in solution, showing a high value of association constant, that is, 3380 M-1 for MRN/HP-ß-CD and 2870 M-1 for MRN/SBE-ß-CD. In vivo biological studies on chick embryo chorioallantoic membrane (CAM) and zebrafish embryo models demonstrated the high biocompatibility of the inclusion complexes and the effective increase in antiangiogenic activity of complexed MRN with respect to the free drug.

3.
Biomolecules ; 12(11)2022 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-36421730

RESUMO

Bicalutamide (BCL) is a nonsteroidal antiandrogen drug that represents an alternative to castration in the treatment of prostate cancer, due to its relatively long half-life and tolerable side effects. However, it possesses a very low water solubility that can affect its oral bioavailability. In this work, we developed inclusion complexes of BCL with the highly soluble hydroxypropyl-ß-cyclodextrin (HP-ß-CyD) and sulfobutylether-ß-cyclodextrin (SBE-ß-CyD) to increase the water solubility and anticancer activity of BCL. The inclusion complexes were prepared using the freeze-drying method and were then characterized in a solid state via differential scanning calorimetry and X-ray analysis and in solution via phase-solubility studies and UV-vis and NMR spectroscopy. The BCL/HP-ß-CyD and BCL/SBE-ß-CyD inclusion complexes were amorphous and rapidly dissolved in water. Both the 1H-NMR spectra and molecular modeling studies confirmed the penetration of the 2-(trifluoromethyl)benzonitrile ring of BCL within the cavity of both cyclodextrins (CyDs). Due to the consistent improvement of the water solubility of BCL, the inclusion complexes showed higher antiproliferative activity toward the human prostate androgen-independent cell lines, DU-145 and PC-3, with respect to free BCL. These results demonstrate the ability of HP-ß-CyD and SBE-ß-CyD to complex BCL, permitting the realization of liquid formulations with potentially high oral bioavailability and/or possible parenteral administration.


Assuntos
Ciclodextrinas , Masculino , Humanos , Ciclodextrinas/farmacologia , Ciclodextrinas/química , Nitrilas/farmacologia , Solubilidade , 2-Hidroxipropil-beta-Ciclodextrina/farmacologia , Água/química
4.
Biomolecules ; 9(10)2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31557949

RESUMO

Idebenone (IDE) is an antioxidant drug active at the level of the central nervous system (CNS), whose poor water solubility limits its clinical application. An IDE/2-hydroxypropyl-ß-cyclodextrin (IDE/HP-ß-CD) inclusion complex was investigated by combining experimental methods and theoretical approaches. Furthermore, biological in vitro/ex vivo assays were performed. Phase solubility studies showed an AL type diagram, suggesting the presence of a 1:1 complex with high solubility. Scanning electron microscopy (SEM) allowed us to detect the morphological changes upon complexation. The intermolecular interactions stabilizing the inclusion complex were experimentally characterized by exploring the complementarity of Fourier-transform infrared spectroscopy in attenuated total reflectance geometry (FTIR-ATR) with mid-infrared light, Fourier-transform near-infrared (FT-NIR) spectroscopy, and Raman spectroscopy. From the temperature evolution of the O-H stretching band of the complex, the average enthalpy ΔHHB of the hydrogen bond scheme upon inclusion was obtained. Two-dimensional (2D) rotating frame Overhauser effect spectroscopy (ROESY) analysis and computational studies involving molecular modeling and molecular dynamics (MD) simulation demonstrated the inclusion of the quinone ring of IDE inside the CD ring. In vitro/ex vivo studies evidenced that complexation produces a protective effect of IDE against the H2O2-induced damage on human glioblastoma astrocytoma (U373) cells and increases IDE permeation through the excised bovine nasal mucosa.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/farmacologia , Antioxidantes/farmacologia , Ubiquinona/análogos & derivados , 2-Hidroxipropil-beta-Ciclodextrina/química , Animais , Antioxidantes/química , Bovinos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , L-Lactato Desidrogenase/análise , L-Lactato Desidrogenase/metabolismo , Modelos Moleculares , Relação Estrutura-Atividade , Ubiquinona/química , Ubiquinona/farmacologia
5.
Carbohydr Polym ; 206: 792-800, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30553385

RESUMO

We investigated the complexation of celecoxib (CCB) into sulfobuthyl-ether-ß-cyclodextrin (SBE-ß-CD) for the realization of an inhalable dry-powder formulation containing gemcitabine (GEM) for lung anticancer therapy. Complexation increased the water solubility of CCB (0.003 mg/mL and 0.834 mg/mL for CCB free and complexed, respectively) and produced a quantitative dissolution of the drug within 15 min. The CCB/SBE-ß-CD inclusion complex showed a high stability constant (8131 M-1) not influenced by the presence of GEM in solution. Two-dimensional NMR experiments and computational studies demonstrated that the pyrazole ring of CCB penetrates deeper into SBE-ß-CD from the secondary rim. The aromatic rings are positioned at the edge of the cavity, establishing hydrogen bonds with the SBE-ß-CD that stabilized the complex. CCB showed limited cytotoxic activity on A549 cell lines. Complexation significantly increased activity passing from 30% to 45% cell mortality. Moreover, CCB/SBE-ß-CD strongly improved the cytotoxicity of GEM, observing about 60% of cell mortality for the combined formulation.


Assuntos
Antineoplásicos/farmacologia , Celecoxib/química , Desoxicitidina/análogos & derivados , beta-Ciclodextrinas/química , Células A549 , Antineoplásicos/química , Desoxicitidina/química , Desoxicitidina/farmacologia , Composição de Medicamentos , Sinergismo Farmacológico , Humanos , Simulação de Dinâmica Molecular , Pós , Solubilidade , Água/química , Gencitabina
6.
Eur J Med Chem ; 143: 583-590, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29207341

RESUMO

((3RS,5SR)- and ((3RS,5RS)-2-(2-methoxybenzyl)-3-(1,10-phenanthrolin-2-yl)isoxazolidin-5-yl)methanol have been synthesized, according to 1,3-dipolar cycloaddition methodology, as DNA intercalating agents and evaluated for their anticancer activity against human cervical carcinoma HeLa and head and neck squamous cells carcinoma cell lines. The synthesized compounds exhibited good cytotoxic activity with IC50 better than cisplatin, used as the main and effective treatment for HNSCC, and a 24.3-72.0-fold selectivity respect to the 184B5 non-cancerous immortalized breast epithelial cell lines. Unwinding assay, circular dichroism data, and Uv-vis melting experiments confirmed that these compounds act as DNA intercalators with a binding constant in the order of 104 M-1. Docking studies showed that both compounds can interact as intercalating agent with both poly-d(AT)2 and poly-d(GC)2, preferring an entrance by the minor groove of the poly-d(AT)2.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/farmacologia , DNA de Neoplasias/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Substâncias Intercalantes/farmacologia , Isoxazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/química , DNA de Neoplasias/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Isoxazóis/síntese química , Isoxazóis/química , Modelos Moleculares , Estrutura Molecular , Carcinoma de Células Escamosas de Cabeça e Pescoço , Relação Estrutura-Atividade
7.
Chem Biol Drug Des ; 91(2): 519-525, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28941159

RESUMO

In this paper, we investigated the hypothesis that pseudouridine isoxazolidinyl nucleoside analogues could act as potential inhibitors of the pseudouridine 5'-monophosphate glycosidase. This purpose was pursued using molecular modeling and in silico ADME-Tox profiling. From these studies emerged that the isoxazolidinyl derivative 1 5'-monophosphate can be effectively accommodated within the active site of the enzyme with a ligand efficiency higher than that of the natural substrate. In this context, the poor nucleofugality of the N-protonated isoxazolidine prevents or slows down, the first mechanistic step proposed for the degradation of the pseudouridine 5'-monophosphate glycosidase, leading to the enzyme inhibition. Finally, the results of the physicochemical and ADME-Tox informative analysis pointed out that compound 1 is weakly bounded to plasma protein, only moderately permeate the blood-brain barrier, and is non-carcinogen in rat and mouse. To the best of our knowledge, this is the first paper that introduces the possibility of inhibition of pseudouridine 5'-monophosphate glycosidase by a molecule that competing with the natural substrate hinders the glycosidic C-C bond cleavage.


Assuntos
Glicosídeo Hidrolases/antagonistas & inibidores , Isoxazóis/química , Simulação de Acoplamento Molecular , Nucleosídeos/análogos & derivados , Pseudouridina/química , Sítios de Ligação , Barreira Hematoencefálica/metabolismo , Domínio Catalítico , Glicosídeo Hidrolases/metabolismo , Ligação de Hidrogênio , Nucleosídeos/metabolismo , Termodinâmica
8.
J Med Chem ; 60(23): 9531-9544, 2017 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-29172528

RESUMO

This contribution reports the synthesis and evaluation of novel hybrid compounds that conjugate a sigma (σ) receptor pharmacophore and a nitric oxide (NO) photodonor. All compounds preserve their capability to generate NO under visible light and possess overall σ receptor nanomolar affinity, with one of them (8b) exhibiting remarkable σ2 receptor selectivity. Compounds 8b, 11a, and 11b were tested on tumorigenic MCF-7 and A2058 cells expressing high levels of σ2 and σ1 receptor, respectively. Considerable loss of cell viability was detected under light excitation, while negligible effects in the dark were detected. Moreover, they did not show any significant cytotoxicity in the dark or under irradiation on nontumorigenic NCTC-2544 keratinocytes. NO-induced reduction of cellular viability was demonstrated by in-cell NO detection and total nitrite estimation. For the first time, a combination of σ receptor moieties and a NO photodonor is reported, providing distinctive ligands potentially useful for cancer management.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Doadores de Óxido Nítrico/química , Doadores de Óxido Nítrico/farmacologia , Receptores sigma/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Luz , Células MCF-7 , Neoplasias/metabolismo , Óxido Nítrico/metabolismo , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia
9.
Eur J Med Chem ; 141: 188-196, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29031066

RESUMO

Histone deacetylase inhibitors (HDACis) play an important role as valuable drugs targeted to cancer therapy: several HDACis are currently being tested in clinical trials. Two new potential HDACis 1a and 1d, characterized by the presence of a biphenyl-4-sulfonamide group as a connection unit between the N-{4-[(E)-(2-formylhydrazinylidene)methyl]-3-hydroxyphenyl} and the 2-hydroxy-N-(trifluoroacetyl)benzamide moiety, respectively, as two zinc-binding group (ZBG), have been designed, synthesized and tested for their biological activity. Surprisingly, compounds 1a and 12, this last exclusively obtained in place of 1d, exhibited a very low HDAC inhibitory activity. A serendipitous assay of these two compounds, conducted on three chemoresistant cell lines of head and neck squamous cell carcinoma (HNSCC), showed their antiproliferative activity at low nanomolar concentrations, better than cisplatin. In vitro, biological assays indicated that compounds 1a and 12 are able to increase acetylation of histone H3 and to interfere with the PI3K/Akt/mTOR pathway by inducing the accumulation of PTEN protein.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Descoberta de Drogas , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Inibidores de Histona Desacetilases/farmacologia , Sulfonamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Carcinoma de Células Escamosas/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias de Cabeça e Pescoço/patologia , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
10.
ACS Med Chem Lett ; 8(8): 881-885, 2017 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-28835806

RESUMO

The role of nitric oxide (NO) as an antimicrobial and anticancer agent continues to stimulate the search of compounds generating NO in a controlled fashion. Photochemical generators of NO are particularly appealing due to the accurate spatiotemporal control that light-triggering offers. This contribution reports a novel molecular construct in which multiple units of 3-(trifluoromethyl)-4-nitrobenzenamine NO photodonor are clustered and spatially organized by covalent linkage to a calix[4]arene scaffold bearing two quaternary ammonium groups at the lower rim. This multivalent calix[4]arene-NO donor conjugate is soluble in hydro-alcoholic solvent where it forms nanoaggregates able to release NO under the exclusive control of visible light inputs. The light-stimulated antibacterial activity of the nanoconstruct is demonstrated by the effective bacterial load reduction of Gram-positive Staphylococcus aureus ATCC 6538 and Gram-negative Escherichia coli ATCC 10536.

11.
Mater Sci Eng C Mater Biol Appl ; 46: 470-81, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25492012

RESUMO

Within a research directed to developing new polymeric materials, suitable for decorating the surface of colloidal drug carriers, PEG5000 polymers containing a free carboxyl or amine group at one end were conjugated to an α-lipoamino moiety (LAA). The conjugates were characterized by FT-IR, (1)H-NMR, and MALDI-TOF mass spectrometry. They showed the same profile of solubility as the parent PEGs in water and in some polar and apolar solvents of pharmaceutical use. Representative terms showed to be well tolerated when incubated with Caco-2 or L929 cell cultures. Dedicated differential scanning calorimetry (DSC) studies were performed to prove the interaction of increasing molar fractions of the PEG5000-LAA conjugates with dipalmitoylphosphatidylcholine (DPPC) bilayers, to gain information about their possible incorporation in drug nanocarriers. While the parent PEGs affected only the superficial structure of bilayers, the amphiphilic PEG-LAA conjugates induced a perturbing effect on the thermotropic behavior of DPPC liposomes, according to the structure of the linked LAA residue. A molar concentration of these PEG-LAA between 5 and 10% was individuated as the most suitable to produce stable vesicles.


Assuntos
Aminoácidos/química , Coloides , Portadores de Fármacos , Polietilenoglicóis/química , Materiais Biocompatíveis , Células CACO-2 , Varredura Diferencial de Calorimetria , Humanos , Espectroscopia de Prótons por Ressonância Magnética , Espectrofotometria Infravermelho , Análise Espectral , Propriedades de Superfície
12.
Eur J Med Chem ; 74: 95-115, 2014 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-24448420

RESUMO

The interaction of small molecules with DNA plays an essential role in many biological processes. As DNA is often the target for majority of anticancer and antibiotic drugs, study about the interaction of drug and DNA has a key role in pharmacology. Moreover, understanding the interactions of small molecules with DNA is of prime significance in the rational design of more powerful and selective anticancer agents. Two of the most important and promising targets in cancer chemotherapy include DNA alkylating agents and DNA intercalators. For these last the DNA recognition is a critical step in their anti-tumor action and the intercalation is not only one kind of the interactions in DNA recognition but also a pivotal step of several clinically used anti-tumor drugs such as anthracyclines, acridines and anthraquinones. To push clinical cancer therapy, the discovery of new DNA intercalators has been considered a practical approach and a number of intercalators have been recently reported. The intercalative binding properties of such molecules can also be harnessed as diagnostic probes for DNA structure in addition to DNA-directed therapeutics. Moreover, the problem of intercalation site formation in the undistorted B-DNA of different length and sequence is matter of tremendous importance in molecular modeling studies and, nowadays, three models of DNA intercalation targets have been proposed that account for the binding features of intercalators. Finally, despite DNA being an important target for several drugs, most of the docking programs are validated only for proteins and their ligands. Therefore, a default protocol to identify DNA binding modes which uses a modified canonical DNA as receptor is needed.


Assuntos
DNA/química , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/farmacologia , Animais , Linhagem Celular Tumoral , Humanos , Substâncias Intercalantes/química , Simulação de Acoplamento Molecular
13.
Bioorg Med Chem ; 20(11): 3652-7, 2012 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-22549138

RESUMO

Truncated phosphonated C-1'-branched N,O-nucleosides have been synthesized in good yields by 1,3-dipolar cycloaddition methodology, starting from N-methyl-C-(diethoxyphosphoryl)nitrone 7. Preliminary biological assays show that ß-anomers are able to inhibit HIV in vitro infection at concentrations in the micromolar range. Higher SI values with respect to AZT indicated that the compounds were endowed with low cytotoxicity.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Antivirais/química , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Infecções por HIV/tratamento farmacológico , Vírus Linfotrópico T Tipo 1 Humano/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Leucócitos Mononucleares/virologia , Estrutura Molecular , Óxidos de Nitrogênio/química , Nucleosídeos/química , Fenômenos de Química Orgânica , Organofosfonatos/química , Relação Estrutura-Atividade , Zidovudina/farmacologia
14.
J Med Chem ; 46(17): 3696-702, 2003 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-12904074

RESUMO

Enantiomers of 4'-aza-2',3'-dideoxynucleosides have been prepared by two different synthetic approaches, on the basis of 1,3-dipolar cycloaddition of a chiral nitrone. Cytotoxicity and apoptotic activity have been investigated. (5'S)-5-Fluoro-1-isoxazolidin-5-yl-1H-pyrimidine-2,4-dione [(-)-AdFU], while showing low level of cytotoxicity, is a good inductor of apoptosis on lymphoid and monocytoid cells, acting as a strong potentiator of Fas-induced cell death.


Assuntos
Didesoxinucleosídeos/síntese química , Isoxazóis/síntese química , Uridina/síntese química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Antivirais/síntese química , Antivirais/farmacologia , Antivirais/toxicidade , Apoptose , Caspase 3 , Caspase 8 , Caspase 9 , Inibidores de Caspase , Caspases/metabolismo , Linhagem Celular , Didesoxinucleosídeos/farmacologia , Didesoxinucleosídeos/toxicidade , Humanos , Isoxazóis/farmacologia , Isoxazóis/toxicidade , Tecido Linfoide/citologia , Conformação Molecular , Monócitos/citologia , Teoria Quântica , Estereoisomerismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Uridina/análogos & derivados , Uridina/farmacologia , Uridina/toxicidade , Receptor fas/fisiologia
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