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1.
Mini Rev Med Chem ; 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33402082

RESUMO

Among many reactive oxygen species (ROS) which are constantly generated during oxidative stress in cellular membranes, formation and subsequent reactivity of ubiquitous 4-hydroxy-2-nonenal (HNE) with nearby amino acids and lipids represents one of the main research targets in cell physiology in the last decades. Starting from the first synthesis of HNE in 1967, chemistry and reactivity of HNE are constantly under intense scrutiny. This review shows recent advances in the field which are discussed with the special emphasis on revealing intricate details of numerous reaction mechanisms of HNE with lipids and amino acids, with the goal of understanding the reactivity of HNE at the molecular level.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33404073

RESUMO

BACKGROUND: Antibiotic resistance is increasing day by day, thereby increase the chances of more infections by resistant bacteria. In this situation, antimicrobial photodynamic therapy (aPDT) is gaining more attraction. OBJECTIVE: To evaluate the antimicrobial effect of ALA derivatives using photodynamic therapy. MATERIALS AND METHODS: In this study, we evaluated the aPDT effect of different derivatives of 5-ALA. In vivo and in vitro studies were performed to measure the antimicrobial activity. Different light doses and different concentrations of drugs were used to test anti-bacterial effect of drugs as well as to detect any physiological changes in animal model after the treatment. RESULTS: In vivo studies revealed that ALA-methyl ester, ALA-hexyl ester, and ALA-13A are potent photosensitizers. In vitro studies involved wound healing rate, body weight, and dietary intake were evaluated, and results showed that ALA, ALA-methyl ester, ALA-hexyl ester, and ALA-13A had good anti-bacterial effects, fast healing rate, and no effect on other physical parameters. CONCLUSION: Photodynamic therapy is increasingly used to treat different types of skin infections caused by bacterial strains. Our studies revealed that ALA-methyl ester, ALA-hexyl ester, and ALA-13A are promising photosensitizers for photodynamic therapy to inhibit the growth of resistant bacterial strains.

3.
Beilstein J Org Chem ; 15: 1313-1320, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31293680

RESUMO

Friedel-Crafts (FC) acylation reactions were exploited in the preparation of ketone-functionalized aromatics. Environmentally more friendly, solvent-free mechanochemical reaction conditions of this industrially important reaction were developed. Reaction parameters such as FC catalyst, time, ratio of reagents and milling support were studied to establish the optimal reaction conditions. The scope of the reaction was explored by employment of different aromatic hydrocarbons in conjunction with anhydrides and acylation reagents. It was shown that certain FC-reactive aromatics could be effectively functionalized by FC acylations carried out under ball-milling conditions without the presence of a solvent. The reaction mechanism was studied by in situ Raman and ex situ IR spectroscopy.

4.
Eur J Med Chem ; 177: 144-152, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31132530

RESUMO

Effective photosensitizers are particularly important factor in clinical photodynamic therapy (PDT). However, there is a scarcity of photosensitizers for simultaneous cancer photo-diagnosis and targeted PDT. Herein, two novel dimethyl 2-(guanidinyl)ethylamino chlorin e6 photosensitizers were synthesized and their efficacy in PDT in A549 tumor was investigated. It was shown that compounds 3 and 4 have a long absorption wavelength in the near infrared region and strong fluorescence emission with slow photo-bleaching rate and markedly strong ability of 1O2 generation. They exhibited lower cytotoxicity and higher photo-cytotoxicity in vitro compared to the known anticancer drug m-THPC in MTT assay in A549 lung cancer cell lines. Compound 4 exhibit better inhibition effect than compound 3 and the IC50 value of compound 4 was 0.197 µM/L under 2 J/cm2 laser irradiation, while compound 3 showed better anti-tumor effects compared to compound 4 in vivo. Intracellular ROS generation was found to be responsible for apoptotic cell death in DCFDA assay. Subcellular localization confirmed the damage site of compounds 3 and 4 in PDT. These findings suggest that the two novel photosensitizers might serve as potential photosensitizers for improved therapeutic efficiency of PDT.


Assuntos
Antineoplásicos/farmacologia , Guanidinas/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Células A549 , Adenocarcinoma Bronquioloalveolar/patologia , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Feminino , Guanidinas/síntese química , Humanos , Neoplasias Pulmonares/patologia , Lisossomos/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Mitocôndrias/metabolismo , Necrose , Fármacos Fotossensibilizantes/síntese química , Porfirinas/síntese química , Oxigênio Singlete/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
5.
J Org Chem ; 84(2): 526-535, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30543108

RESUMO

We revisit the mechanism of reaction between a model lysine side chain and reactive aldehyde 4-hydroxynonenal in different solvents with an increasing water content. We show by model organic reactions and qualitative spectrometric analysis that a nonpolar pyrrole adduct is dominantly formed in non-aqueous solvents dichloromethane and acetonitrile. On the other hand, in aqueous acetonitrile and neat water, other polar products are also isolated, including Michael adducts, hemiacetal adducts, and pyridinium salt adducts, at the same time as the ratio of nonpolar products to polar products is decreasing. The experiments are supported by detailed quantum chemical calculations of the reaction mechanism with different computational setups showing that the pyrrole adduct is the most thermodynamically stable product compared to Michael adducts and hemiacetal adducts and also indicating that water molecules released along the reaction pathway are catalyzing reaction steps involving proton transfer. Finally, we also identify the mechanism of the pyridinium salt adduct that is formed only in aqueous solutions.

6.
Molecules ; 23(12)2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30513686

RESUMO

Mechanochemical ball milling catalytic transfer hydrogenation (CTH) of aromatic nitro compounds using readily available and cheap ammonium formate as the hydrogen source is demonstrated as a simple, facile and clean approach for the synthesis of substituted anilines and selected pharmaceutically relevant compounds. The scope of mechanochemical CTH is broad, as the reduction conditions tolerate various functionalities, for example nitro, amino, hydroxy, carbonyl, amide, urea, amino acid and heterocyclic. The presented methodology was also successfully integrated with other types of chemical reactions previously carried out mechanochemically, such as amide bond formation by coupling amines with acyl chlorides or anhydrides and click-type coupling reactions between amines and iso(thio)cyanates. In this way, we showed that active pharmaceutical ingredients Procainamide and Paracetamol could be synthesized from the respective nitro-precursors on milligram and gram scale in excellent isolated yields.


Assuntos
Hidrocarbonetos Aromáticos/química , Nitrocompostos/química , Compostos de Anilina/química , Catálise , Hidrogenação , Espectroscopia de Infravermelho com Transformada de Fourier
7.
Bioorg Med Chem Lett ; 28(10): 1785-1791, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29673979

RESUMO

A novel 131-pyridine substituted chlorin e6 derivative (Chlorin A) was synthesized. It has characteristic long wavelength absorption at 664 nm and the emission wavelength at 667 nm. The generation rate of singlet oxygen of this compound is higher than Temoporfin. In vitro, Chlorin A showed higher phototoxicity against the human esophageal cancer cells than Temoporfin while with lower dark-toxicity. Its accumulation effect in mitochondria, lysosomes and endoplasmic reticulum was traced in subcellular localization tests. In flow cytometry obvious apoptosis cells were observed after 2 h irradiation. Significant in vivo photodynamic anti-tumor efficacy was also exhibited on mice bearing esophageal cancer. So Chlorin A could be suggested as a promising anti-tumor drug candidate in photodynamic therapy.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Esofágicas/tratamento farmacológico , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Piridinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Neoplasias Esofágicas/patologia , Humanos , Camundongos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Porfirinas/síntese química , Porfirinas/química , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade
8.
Chempluschem ; 83(9): 845-854, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31950687

RESUMO

A series of benzoylguanidinium salts was prepared and the changes in UV/Vis spectra, triggered by the presence of anions, were investigated. All compounds undergo deprotonation with basic anions like dihydrogenphosphate and acetate in acetonitrile. The most pronounced spectral changes were obtained by deprotonation of N1 -benzoyl-N3 -(p-nitrophenyl) guanidinium chloride which shows the naked-eye visible color change from colorless to yellow. Measured pKa (BH+ ) in acetonitrile ranges from 12-16, which is comparable to the pyridinium cations. The proton transfer equilibria were also tested in acetonitrile/water mixture where all but the most acidic derivatives showed pKa (BH+ ) of 4-6 units which corresponds to apparent association constants of 104 -106  dm3 mol-1 . UV/Vis spectra of neutral and protonated forms were modelled by the TD-DFT approach using CAM-B3LYP and PBE0 functionals and compared to CC2 results. In the case of CAM-B3LYP, a parameter ω, defining amount of long-range exchange correction, was varied to achieve the best agreement with the experimental spectra. The optimized ω parameters are 0.10 a0 -1 for neutral benzoylguanidines and 0.20 a0 -1 for neutral nitrobenzoyl and protonated systems. The larger ω parameter in the latter is ascribed to more pronounced charge transfer character of the HOMO-LUMO transition - the one responsible for the lowest energy absorption band.

9.
Beilstein J Org Chem ; 13: 1745-1752, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28904618

RESUMO

The mechanochemical N-alkylation of imide derivatives was studied. Reactions under solvent-free conditions in a ball mill gave good yields and could be put in place of the classical solution conditions. The method is general and can be applied to various imides and alkyl halides. Phthalimides prepared under ball milling conditions were used in a mechanochemical Gabriel synthesis of amines by their reaction with 1,2-diaminoethane.

10.
Chem Res Toxicol ; 30(3): 840-850, 2017 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-28222263

RESUMO

4-Hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE) are biologically important reactive aldehydes formed during oxidative stress in phospholipid bilayers. They are highly reactive species due to presence of several reaction centers and can react with amino acids in peptides and proteins, as well as phosphoethanolamine (PE) lipids, thus modifying their biological activity. The aim of this work is to study in a molecular detail the reactivity of HNE and ONE toward PE lipids in a simplified system containing only lipids and reactive aldehydes in dichloromethane as an inert solvent. We use a combination of quantum chemical calculations, 1H NMR measurements, FT-IR spectroscopy, and mass spectrometry experiments and show that for both reactive aldehydes two types of chemical reactions are possible: formation of Michael adducts and Schiff bases. In the case of HNE, an initially formed Michael adduct can also undergo an additional cyclization step to a hemiacetal derivative, whereas no cyclization occurs in the case of ONE and a Michael adduct is identified. A Schiff base product initially formed when HNE is added to PE lipid can also further cyclize to a pyrrole derivative in contrast to ONE, where only a Schiff base product is isolated. The suggested reaction mechanism by quantum-chemical calculations is in a qualitative agreement with experimental yields of isolated products and is also additionally investigated by 1H NMR measurements, FT-IR spectroscopy, and mass spectrometry experiments.


Assuntos
Aldeídos/química , Fosfatidiletanolaminas/química , Espectrometria de Massas , Espectroscopia de Prótons por Ressonância Magnética , Espectroscopia de Infravermelho com Transformada de Fourier
11.
Angew Chem Int Ed Engl ; 56(11): 3090-3093, 2017 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-28229512

RESUMO

Herein we present the first superbase MHPN with two interacting P-ylide entities. Unlike classical proton sponges, this novel compound class has carbon atoms as basicity centers which are forced into close proximity by a naphthalene scaffold. The bisylide exhibits an experimental pKBH+  value of 33.3±0.2 on the MeCN scale and a calculated gas-phase proton affinity of 277.9 kcal mol-1 (M062X/6-311+G**//M062X/6-31G*+ZPVE method) exceeding that of the corresponding monoylide by nearly 15 kcal mol-1 . The origin of the unexpectedly high basicity of the new bisylide was investigated by NMR spectroscopic methods, single-crystal X-ray diffraction as well as theoretical calculations and can be partly attributed to the rapid exchange of the "acidic" proton between the two basic carbon atoms after protonation.

12.
J Phys Chem A ; 120(36): 7088-100, 2016 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-27556411

RESUMO

UV/vis spectra of phenylguanidine (PHGU) in the gas phase and in acetonitrile have been simulated by TD-DFT calculations. Several DFT hybrid and long-range corrected functionals were tested with respect to CASPT2 gas phase calculations. Solvent effects were considered using polarizable continuum model (PCM) and compared with the measured data in acetonitrile. Comparison with isoelectronic phenylurea and related phenyltiourea was done as well. The PBE0 and long-range corrected CAM-B3LYP functionals were selected to investigate the effect of protonation on the excitation energies and absorption intensities of PHGU and several guanidine derivatives with different aromatic chromophoric groups (naphthyl, anthracenyl, quinolinyl, anthraquinonyl, and coumarinyl). Also, the effect of complexation and specific interactions through hydrogen bonds with different anions was examined. It was shown that the protonation of the guanidine subunit shifts the low energy absorption bands toward higher energies (hypsochromic shift). The shift is reduced upon complexation with anions. In phenylguanidine salts, λmax values are correlated to the anion basicity and strength of H-bonding. The observed changes diminish upon increase of chromophoric size (naphthyl, anthracenyl). Theoretical predictions of UV/vis spectra correlate well with experimentally measured spectra of selected guanidine derivatives and their salts.


Assuntos
Guanidina/química , Espectrofotometria Ultravioleta/métodos , Acetonitrilos/química , Antracenos/química , Antraquinonas/química , Guanidinas/química , Ligação de Hidrogênio , Modelos Químicos , Naftalenos/química , Quinolinas/química , Solventes/química
13.
Chempluschem ; 81(9): 985-994, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31968805

RESUMO

Self-assembled bis(zinc porphyrin)-bispyridinopyrrolidinofullerene coordination complexes were obtained in solution. Two [5]polynorbornane-bridged bis-porphyrins were used that differed in the arms containing porphyrin units: whereas 1 has rigid [5]polynorbornane linkers, compound 2 has additional flexible propyl chains. The different geometries of the two hosts affect both the complexation process and the photoreactivity of the final product. Formation of the complexes, characterized by absorption, emission, and NMR spectroscopy, occurs with association constants in the order of 104 and 106 m-1 for bis-porphyrin tweezers 1 and 2, respectively. The higher flexibility of tweezers 2 accounts for the greater association ability. Full photophysical characterization of the complexes, as well as of suitable models, has been performed by means of steady-state and time-resolved optical spectroscopy. Ultrafast luminescence detection and pump-probe transient absorption analysis were used to investigate photoinduced processes within the complexes. The results provide evidence that an electron-transfer process from the bis-porphyrin host to the fullerene guest occurs in both complexes, and a slightly longer lifetime of the charge-separated state is observed in the complex with more flexible host 2.

14.
Tumour Biol ; 37(5): 6923-33, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26662801

RESUMO

A novel porphyrin derivative, 5, 10, 15, 20-tetrakis (5-morpholinopentyl)-21H, 23H-Porphin (MPP, 4) and its photophysical characteristics, therapeutic efficacy of photodynamic therapy (PDT) in vitro and in vivo, tumor selectivity, and clearance from normal tissues were investigated here. MPP has strong absorption at relatively long wavelength (λmax = 648 nm, molar absorption coefficient ε ∼ 17,200 M(-1)cm(-1)) and can emit strong fluorescence at 653 and 718 nm. When administered to the animal tumor models by tail vein injection, MPP was capable of accumulating in the tumor site, as examined in vivo with the fluorescence signal of MPP. By the combination of MPP and a 650-nm laser irradiation, the viability of T24 cells could decrease by 4.37 %, and inhibition rate of T24 tumor could increase up to 91.21 % compared with control group, demonstrating the potential of MPP as an effective photosensitizer in PDT for tumor treatment.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Fotoquimioterapia , Porfirinas/síntese química , Porfirinas/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Análise Espectral , Distribuição Tecidual , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Chem Commun (Camb) ; 48(99): 12100-2, 2012 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-23135220

RESUMO

Environmentally friendly one-pot synthesis of amides, bis-amides and dipeptides by mechanochemical carbodiimide-mediated coupling of carboxylic acids and amines is described; high reaction yields and simple aqueous work-up allow for the clean, practical and fast preparation of a variety of compounds containing the amide bond from readily accessible reagents.


Assuntos
Amidas/química , Aminas/química , Ácidos Carboxílicos/química , Dipeptídeos/química , Amidas/síntese química , Carbodi-Imidas/química , Água/química
16.
Chem Commun (Camb) ; 48(78): 9705-7, 2012 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-22914574

RESUMO

ortho- and para-Phenylenediamines were desymmetrised and quantitatively transformed into mono- and bis-(thio)ureas or mixed thiourea-ureas through a one-pot mechanochemical click reaction sequence; mechanochemical desymmetrisation proceeds quantitatively without excess reagents and allows the controlled extension of a molecular structure by combining normally competing reactions.


Assuntos
Fenilenodiaminas/química , Tioureia/síntese química , Química Click , Estrutura Molecular , Estereoisomerismo , Tioureia/química
17.
Org Biomol Chem ; 9(19): 6771-8, 2011 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-21850327

RESUMO

The first example of thermal (8π,6π)-electrocyclisation of 1,3,5,7-octatetraene with one double bond embedded in an aromatic moiety is described. By this process, [3,4]-benzo-8-substituted octatetraene derivatives, the cis,trans-1-(o-vinylphenyl)-4-(R = Me, Ph, 2-furyl)buta-1,3-dienes were transformed to a new endo-7-(R = Me, Ph, 2-furyl) and exo-7-(R = Me)-2,3-benzobicyclo[4.2.0]octa-2,4-dienes. Mechanism of reaction was also studied by DFT quantum-chemical calculations. The M06/6-311+G(d,p)//M06/6-31+G(d,p) calculations indicate that formation of the single endo-isomer in the case of phenyl and 2-furyl substituents is determined by higher activation barriers for exo-6π-electrocyclisation than for 8π-cycloreversion.


Assuntos
Ciclo-Octanos/química , Teoria Quântica , Temperatura , Ciclização , Ciclo-Octanos/síntese química , Estrutura Molecular , Estereoisomerismo
18.
Mol Divers ; 15(2): 541-60, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-20857195

RESUMO

This article describes novel synthetic approaches to polynorbornene molecular scaffolds substituted with peptides at various, well-defined positions. A library of norbornene building blocks with attached peptides was prepared. Alkene cyclobutane epoxide (ACE) coupling method was used as a key step reaction for the connection of two norbornene building blocks into bis-peptide scaffolds. Photodimerization of cyclobutene diesters offers an alternative route to polynorbornene bis-peptides. Pyrrolo-peptides were used for preparation of peptide-substituted 7-aza norbornenes. Asymmetrical bis-peptide scaffolds were prepared by ACE coupling of peptide-norbornane epoxide with another norbornene-peptide block. Chemical elaboration of bridgehead dimethyl esters of ACE products or epoxide ACE reagents was also used for peptide attachment.


Assuntos
Norbornanos/química , Peptídeos/química , Peptídeos/síntese química , Modelos Moleculares , Peptidomiméticos
19.
J Org Chem ; 69(21): 7134-42, 2004 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-15471462

RESUMO

Density functional theory (B3LYP/6-31G) was used to study a large series of bridged polycyclic alkenes based on the bicyclo[2.1.1], -[3.2.1], and -[3.2.2] nuclei. In those compounds with pi-facial dissymmetry, butterfly bending of the strained olefinic bonds was generally predicted. Surprisingly, large pyramidalizations are calculated for the highly strained but pi-facially symmetric tetracyclo[5.1.1.1.(3,5)0(2,6)]dec-2-ene (28, psi = 19.8 degrees ) and tetracyclo[5.2.2.1.(3,5)0(2,6)]dodec-2,8,10-triene (33, psi = 14.4 degrees ). The preference for propano-directed bending in the bicyclo[3.2.1]octenes is about as strong as that for endo bending in norbornenes.

20.
J Comput Chem ; 25(4): 542-57, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-14735572

RESUMO

Semiempirical AM1 calculations have been carried out on host-guest complexes of model hemicarcerands 1a and 2a. The justification for the choice of the AM1 Hamiltonian was based on a comparison between reported X-ray data for the smaller tetrabromocavitand 4a and computational results obtained using several different Hamiltonians. The complexation behavior of hemicarcerands 1a and 2a have been compared with experimental results reported by Cram et al. for the related hemicarcerands 1b and 2b. Based on this comparison, a criterion for predicting guest encapsulation was developed, E(complexation), which relies on the calculation of AM1 heats of formation for host, guest, and hemicarceplex. If E(complexation) is lower than 10 kcal/mol, then a guest will be encapsulated, while if it is greater than 30 kcal/mol, a guest will not be encapsulated. The use of constrained-path AM1 optimizations to determine the energy barriers to guest entry and exit from the host was found to be a useful tool for examining suitable host-guest combinations when the E(complexation) criteria does not hold. We have computed the barriers to exit of N, N-dimethylformamide (dmf) and furan from the hemicarcerand 1a, the former has been compared with the experiment and shows excellent agreement. Based on the success of the above computational methods in predicting which host-guest combinations will form stable hemicarceplexes we have synthesized a new target hemicarceplex 1b.furan.

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