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1.
Food Chem ; 304: 125446, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31491715

RESUMO

Fused coumarins recently attracted strong scientific interest due to their potent pharmacological activities. In this study, density functional theory (DFT) calculations were performed to evaluate the antiradical activities of a series of coumarin-fused coumarins. By calculating the thermodynamic parameters, three primary mechanisms including hydrogen atom transfer (HAT), electron transfer followed by proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET) were examined. It was found that in the gas and benzene phases, the studied compounds prefer to undergo HAT mechanism, while SPLET is more favored in polar media. The results also reveal the possibility of double HAT and double SPLET mechanisms for compound CC-6. Interestingly, a new polycyclic compound was generated by forming a new C5-O5' bond during the second HAT process at the 5'-OH in CC-6-R6 radical. In addition, the SPLHAT mechanism is proposed as a competitive pathway for radical scavenging by CC-4, CC-5 and CC-6.

2.
Luminescence ; 34(6): 595-601, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31074200

RESUMO

In this paper, the interactions of pepsin with fluoroquinolones, including norfloxacin (NFX) or ofloxacin (OFX), were investigated using fluorescence spectroscopy. The effects of NFX or OFX on pepsin showed that the molecular conformation of pepsin and the microenvironment of tryptophan residues were changed under mimicked physiological conditions. Static quenching was suggested as a factor. Quenching constants and binding constants were determined and thermodynamic parameters were calculated at three temperatures (25°C, 31°C and 37°C). Molecular interaction distances (binding distance r) were obtained. Binding was enthalpy driven and the process was spontaneous. Synchronous fluorescence, three-dimensional fluorescence spectroscopy and molecular simulation were used for analysis. Interactions were further tested using molecular modelling. Quenching and binding constants of NFX with pepsin were the highest when testing NFX/OFX/fleroxacin/gatifloxacin with pepsin combinations. NFX was the strongest quencher, and affinity of NFX for pepsin was higher than that of OFX/fleroxacin/gatifloxacin.

3.
J Phys Chem A ; 122(43): 8520-8529, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30296082

RESUMO

In view of the multifunctional features of coumarins and chalcones, coumarin-chalcone hybrids have attracted much attention in recent years. Herein, the free radical scavenging activities of a series of coumarin-chalcone hybrids were investigated using the density functional theory (DFT) method. Three main reaction mechanisms were explored: hydrogen atom transfer (HAT), electron transfer followed by proton transfer (SET-PT), and sequential proton loss electron transfer (SPLET). Thermodynamic descriptors associated with these mechanisms were calculated in the gas phase and solvents. The results demonstrate that the predicted antioxidant efficiencies are generally in accordance with the experimental results. HAT is proposed as the thermodynamically favored mechanism in the gas phase and nonpolar solution, while SPLET is preferred in polar media. Our results indicate that compound MPHCC possesses potential for inactivating free radicals via double HAT and double SPLET mechanisms depending upon the polarity of environment. In addition, the SPLHAT mechanism provides an alternative pathway to HAT and SPLET for radical scavenging by MPHCC and OPHCC. The results confirmed the crucial role of hydroxyl groups on the chalcone moiety in trapping radicals. 4'-OH in the catechol group is proposed as the primary target for radical attack.

4.
Analyst ; 143(20): 4860-4869, 2018 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-30128454

RESUMO

Monitoring the fluctuations of endogenous selenocysteine (Sec) in vivo is of significant interest to understand the physiological roles of Sec and the mechanisms of Sec-relevant diseases. Herein, a new near-infrared fluorescent probe, Fsec-1, has been developed for the determination of endogenous Sec in living cells and in vivo. Fsec-1 exhibits large fluorescence enhancement (136-fold) and a remarkably large Stokes shift (195 nm) when reacted with Sec. With the advantages of high sensitivity (a detection limit of 10 nM), good selectivity and low cytotoxicity, Fsec-1 was able to recognize both exogenous and endogenous Sec in living cells. The probe was also successfully applied in visualizing both exogenous and endogenous Sec in living mice. Notably, endogenously generated Sec in living tumors xenografted in nude mice was selectively detected by our reaction-based NIR probe for the first time. These results indicated that our new probe could serve as an efficient tool in monitoring endogenous Sec in vivo and exploring the anticancer mechanism of selenium.

5.
Eur J Med Chem ; 130: 393-405, 2017 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-28279846

RESUMO

In this study, a series of 4-anilinoquinazoline derivatives bearing amino acid moiety were designed, synthesized and evaluated for biological activities. The synthesized compounds were screened for anticancer activity against human hepatocellular carcinoma cell HepG2 using SRB assay. In vitro cell growth inhibition assays indicated that compound 6m exhibited moderate inhibitory activities only against human hepatocellular carcinoma cells HepG2 with IC50 of 8.3 µM. Synthetic derivatives showed excellent selectivity, such as compound 6m demonstrated a strong inhibition of EGFR (IC50 = 0.0032 µM), with selectivity of over 2000-fold over other kinases. Apoptosis analysis revealed that compound 6m caused obvious induction of cell apoptosis. 6m significantly down-regulated the expression of Bcl-2 and up-regulated the expression of Bax, decreased mitochondrial membrane potential (ΔΨm), promoted the mitochondrial cytochrome c release into the cytoplasm, activated caspase-3, and finally induced apoptosis of HepG2 cells. Molecular docking indicated that compound 6m could bind well with EGFR. Therefore, compound 6m may be a potential agent for cancer therapy deserving further research.


Assuntos
Aminoácidos/química , Antineoplásicos/química , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Quinazolinas/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Células Hep G2 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/química
6.
Org Biomol Chem ; 14(40): 9588-9597, 2016 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-27714327

RESUMO

Density functional theory (DFT) calculations were performed to elucidate the mechanism and the origin of the high enantioselectivity of the aza-Henry reaction of isatin-derived N-Boc ketimine catalyzed by a quinine-derived catalyst (QN). The C-C bond formation step is found to be both the rate-determining and the stereo-controlled step. The results revealed the important role of the phenolic OH group in pre-organizing the complex of nitromethane and QN and stabilizing the in situ-generated nitronate and protonated QN. Three possible activation modes for C-C bond formation involving different coordination patterns of catalyst and substrates were studied, and it was found that both the ion pair-hydrogen bonding mode and the Brønsted acid-hydrogen bonding mode are viable, with the latter slightly preferred for the real catalytic system. The calculated enantiomeric excess (ee) favouring the S enantiomer is in good agreement with the experimental result. The high reactivity and enantioselectivity can be ascribed to the cooperative role of the multiple non-covalent interactions, including classical and non-classical H bonding as well as anionπ interactions. These results also highlight the importance of the inclusion of dispersion correction for achieving a reasonable agreement between theory and experiment for the current reaction.

7.
Eur J Med Chem ; 123: 21-30, 2016 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-27474920

RESUMO

Calixarene-based compounds are highly effective therapeutic agents against cancer. This study aims to prepare a series of calix [n]arene (n = 4, 6, 8) polyhydroxyamine derivatives (3a-3m) and to study their potential antitumor activities. The single crystal structure of calixs[4]arene derivative 3a was determined through X-ray diffraction. We assessed the ability of the prepared calix [n]arene polyhydroxyamine derivatives to induce cytotoxicity in six cancer cell lines by performing cancer cell growth inhibition assays. Results demonstrated that compounds 3a-3d achieved IC50 values ranging from 1.6 µM to 11.3 µM. Among the different compounds, 3a and 3b exerted the strongest cytotoxic effect in inhibiting the growth of SKOV3 cells. In relation to the underlying mechanisms of cytotoxic effects, cell cycle analysis revealed that the exposure of SKOV3 cells to 3a induced cell cycle arrest in the G0/G1 phase, suggesting a reduction in DNA synthesis. Immunofluorescent staining indicated that the protein expression levels of caspase-3 and p53 in cells significantly increased, whereas that of Bcl-2 was effectively suppressed. Meanwhile, no significant changes in Bax were observed in SKOV3 cells. These results highlight that calixarene 3a can be further studied as a potential anticancer agent.


Assuntos
Antineoplásicos/química , Calixarenos/química , Animais , Antineoplásicos/farmacologia , Calixarenos/síntese química , Calixarenos/farmacologia , Caspase 3/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cristalografia por Raios X , Citostáticos/síntese química , Citostáticos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/efeitos dos fármacos
8.
Org Biomol Chem ; 14(25): 6024-35, 2016 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-27232108

RESUMO

Chiral N-phosphonyl imines have been proven to be efficient electrophilic acceptors for asymmetric aza-Morita-Baylis-Hillman (aza-MBH) reactions with acrylates under convenient conditions. Thirty examples of ß-amino acrylates were generated in high yields (up to 99.4%) and diastereoselectivity (up to >99 : 1 dr) in an atom-economical fashion. The synthesis was proved to follow the GAP (group-assisted purification) chemistry, i.e., the pure products can be obtained simply by washing the crude products with hexane/ethyl acetate (v/v, 10/1) without the use of chromatography or recrystallization. DFT calculations were also conducted to support an asymmetric induction model accounting for high diastereoselectivity.

9.
J Org Chem ; 81(5): 1806-12, 2016 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-26796292

RESUMO

Cu-catalyzed cross-dehydrogenative coupling (CDC) reaction of thiazoles with THF has been studied with the density functional theory method and kinetic Monte Carlo (kMC) simulations. Our results show that the previously proposed concerted metalation-deprotonation mechanism is unfavorable. On the basis of the DFT calculation and kMC simulation results, a new mechanism is proposed. In the favorable mechanism, the Cu(II) catalyst first combines with the thiazoles, forming an organocopper species that then binds to the THF radical. The rate-limiting step, C-C bond formation, is realized through an intramolecular structural rearrangement. The Cu catalyst works as a matchmaker to render the C-C bond formation. Kinetic Monte Carlo simulations demonstrate that one should be careful with the conclusions drawn simply from the calculated barriers.

10.
Food Chem ; 171: 89-97, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25308647

RESUMO

The free radical scavenging activity of a series of 2,4,5-trimethoxy chalcones has been computationally explored using the density functional theory (DFT) method. Three potential working mechanisms, hydrogen atom transfer (HAT), stepwise electron transfer proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET) have been investigated. The physiochemical parameters including O-H bond dissociation enthalpy (BDE), ionisation potential (IP), proton dissociation enthalpy (PDE), proton affinity (PA) and electron transfer enthalpy (ETE) have been calculated in gas phase and solvents. The order of antioxidant efficiencies predicted theoretically in this work is in good agreement with that reported by experimental results. The results obtained demonstrate that HAT would be the most favourable mechanism in the gas and benzene phases, whereas the SPLET mechanism is the thermodynamically preferred pathway in polar media. In addition, the importance of the A-ring on the radical scavenging capabilities of chalcones was also confirmed.


Assuntos
Antioxidantes/química , Chalconas/química , Transporte de Elétrons , Depuradores de Radicais Livres/química , Oxirredução , Polifenóis/química , Solventes/química , Termodinâmica
11.
Sci Rep ; 4: 5870, 2014 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-25070356

RESUMO

As one of three gasotransmitters, the fundamental signalling roles of hydrogen sulphide are receiving increasing attention. New tools for the accurate detection of hydrogen sulphide in cells and tissues are in demand to probe its biological functions. We report the p-nitrobenzyl-based ratiometric fluorescent probe RHP-2, which features a low detection limit, high selectivity and good photostability. The emission intensity ratios had a good linear relationship with the sulphide concentrations in PBS buffer and bovine serum. Our probe was applied to the ratiometric determination and imaging of endogenous H2S in living cells. Furthermore, RHP-2 was used as an effective tool to measure endogenous H2S in the mouse hippocampus. We observed a significant reduction in sulphide concentrations and downregulated expression of cystathionine ß-synthetase (CBS) mRNA and CBS protein in the mouse hippocampus in a chronic unpredictable mild stress (CUMS)-induced depression model. These data suggested that decreased concentrations of endogenous H2S may be involved in the pathogenesis of chronic stress depression.


Assuntos
Carbamatos/síntese química , Depressão/metabolismo , Corantes Fluorescentes/síntese química , Hipocampo/metabolismo , Sulfeto de Hidrogênio/análise , Sondas Moleculares/síntese química , Naftalimidas/síntese química , Estresse Psicológico/metabolismo , Animais , Bovinos , Cistationina beta-Sintase/genética , Cistationina beta-Sintase/metabolismo , Depressão/diagnóstico , Depressão/etiologia , Depressão/fisiopatologia , Modelos Animais de Doenças , Regulação para Baixo , Expressão Gênica , Hipocampo/fisiopatologia , Humanos , Sulfeto de Hidrogênio/metabolismo , Limite de Detecção , Células MCF-7 , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Espectrometria de Fluorescência/métodos , Estresse Psicológico/complicações , Estresse Psicológico/diagnóstico , Estresse Psicológico/fisiopatologia
12.
Food Chem ; 151: 198-206, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24423521

RESUMO

Quantum chemical calculations based on the density functional theory (DFT) have been employed to study the relationship between the structure and the antioxidant activity of four polyphenolic deoxybenzoins (DOBs) in solvents and the gas phase. The three main working mechanisms, H-atom transfer (HAT), single electron transfer-proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET) have been investigated. The calculated results closely matched experimental values. The results obtained prove that for the HAT mechanism, the most efficient system possessed ortho-dihydroxy functionality. The results suggested that HAT would be the most favourable mechanism for explaining the radical-scavenging activity of polyphenolic DOBs in the gas phase, whereas the SPLET mechanism is the thermodynamically favourable pathway in polar solvents.


Assuntos
Benzoína/análogos & derivados , Antioxidantes , Benzoína/química , Oxirredução , Polifenóis , Prótons , Solventes/química
13.
J Mol Model ; 19(9): 3851-62, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23801254

RESUMO

The free radical scavenging activity of six 2'-hydroxychalcones has been studied in gas phase and solvents using the density functional theory (DFT) method. The three main working mechanisms, hydrogen atom transfer (HAT), stepwise electron-transfer-proton-transfer (ET-PT) and sequential-proton-loss-electron-transfer (SPLET) have been considered. The O-H bond dissociation enthalpy (BDE), ionization potential (IP), proton affinity (PA) and electron transfer energy (ETE) parameters have been computed in gas phase and solvents. The theoretical results confirmed the important role of the B ring in the antioxidant properties of hydroxychalcones. In addition, the calculated results matched well with experimental values. The results suggested that HAT would be the most favorable mechanism for explaining the radical-scavenging activity of hydroxychalcone in gas phase, whereas SPLET mechanism is thermodynamically preferred pathway in aqueous solution.


Assuntos
Antioxidantes/química , Chalconas/química , Modelos Teóricos , Elétrons , Hidrogênio/química , Conformação Molecular , Prótons , Solventes/química , Termodinâmica
14.
Bioorg Med Chem Lett ; 23(12): 3523-30, 2013 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-23664099

RESUMO

Novel pyrazole-benzimidazole derivatives have been designed and synthesized. The entire target compounds were determined against cancer cell lines U937, K562, A549, LoVo and HT29 and were screened for Aurora A/B kinase inhibitory activity in vitro. The compounds 7a, 7b, 7i, 7k and 7l demonstrated significant cancer cell lines and Aurora A/B kinase inhibitory activities. Molecular modeling studies suggested the derivatives have bound in the active site of Aurora A kinase through the formation of four hydrogen bonds. Quantum chemical studies were carried out on these compounds to understand the structural features essential for activity. The cellular activity of 7k was also tested by immunofluorescence.


Assuntos
Aurora Quinase A/antagonistas & inibidores , Aurora Quinase B/antagonistas & inibidores , Benzimidazóis/química , Benzimidazóis/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Aurora Quinase A/química , Aurora Quinase B/química , Benzimidazóis/síntese química , Linhagem Celular Tumoral , Desenho de Drogas , Humanos , Modelos Moleculares , Pirazóis/síntese química , Teoria Quântica , Relação Estrutura-Atividade
15.
Chem Biol Drug Des ; 81(3): 399-407, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23279802

RESUMO

Nine novel 4-aminoquinazoline derivatives were designed and synthesized. Biochemical and cellular analyses demonstrated that most of the derivatives exhibited a strong activity to inhibit Aurora A and B kinases and to suppress the proliferation of a panel of human tumor cell lines (U937, K562, A549, LoVo, and HT29). Quantum chemical studies were also carried out to determine the structural features of these compounds engaged in the inhibition of Aurora kinases.


Assuntos
Antineoplásicos/síntese química , Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Teoria Quântica , Quinazolinas/química , Antineoplásicos/química , Antineoplásicos/toxicidade , Aurora Quinases , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células HT29 , Humanos , Células K562 , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/toxicidade , Estrutura Terciária de Proteína , Proteínas Serina-Treonina Quinases/metabolismo , Quinazolinas/síntese química , Quinazolinas/toxicidade , Relação Estrutura-Atividade
16.
Med Chem ; 9(3): 340-50, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-22920155

RESUMO

Two series of novel phenylaminopyrimidine derivatives were designed and synthesized. All target compounds were determined against the human acute monocytic leukemia cell line U937 and the human chronic myeloid leukemia cell line K562 in vitro. Some of the target compounds demonstrated significant inhibitory activity against both cell lines. Compared with the control drug VX-680, 8a, 8e, 8g, 8h, 8j, and 8k demonstrated more potent antitumor activity. The structures of all target compounds were identified by 1H-NMR, 13C-NMR, IR, MS, and EA.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Desenho de Drogas , Pirimidinas/síntese química , Pirimidinas/farmacologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Células K562 , Piperazinas/química , Piperazinas/farmacologia , Pirimidinas/química , Células U937
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