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1.
Biomed Pharmacother ; 153: 113302, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35724512

RESUMO

Searching for novel antimicrobial agents is up to day topic for many group of researchers due to the fact that each year the number of bacterial strains resistant to currently used medicines increases. Special attention in the scientific literature among various groups of bioactive organic compounds is focused on the antimicrobial activity of hydrazide-hydrazones. Due to this fact presented study is focused on the design, synthesis and in vitro antimicrobial properties of novel hydrazide-hydrazones of 4-iodosalicylic acid. Target compounds were synthesized by the condensation reaction of the hydrazide of 4-iodosalicylic acid with substituted (hetero)aromatic aldehydes. Chemical structure of obtained molecules was confirmed by spectral methods (1H NMR and 13C NMR). Bioactivity screening results revealed interesting antimicrobial properties of tested compounds against reference Gram-positive bacteria and fungi belonging to Candida spp. Especially, hydrazide-hydrazones 3-5 showed very strong or strong bactericidal effect towards some cocci and bacilli (MIC = 7.81-15.62 µg/mL).


Assuntos
Anti-Infecciosos , Hidrazonas , Antibacterianos/química , Anti-Infecciosos/química , Antifúngicos/farmacologia , Bactérias , Bactérias Gram-Positivas , Hidrazinas/farmacologia , Iodobenzoatos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade
2.
J Am Soc Mass Spectrom ; 33(8): 1338-1345, 2022 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34670075

RESUMO

Radical-directed dissociation (RDD) is a powerful technique for structural characterization of peptides in mass spectrometry experiments. Prior to analysis, a radical precursor must typically be appended to facilitate generation of a free radical. To explore the use of a radical precursor that can be easily attached in a single step, we modified peptides using a "click" reaction with iodophenyl isothiocyanate. Coupling with amine functional groups proceeds with high yields, producing stable iodophenylthiourea-modified peptides. Photodissociation yields were recorded at 266 and 213 nm for the 2-, 3-, and 4-iodo isomers of the modifier and found to be highest for the 4-iodo isomer in nearly all cases. Fragmentation of the modified peptides following collisional activation revealed favorable losses of the tag, and electronic structure calculations were used to evaluate a potential mechanism involving hydrogen transfer within the thiourea group. Examination of RDD data revealed that 4-iodobenzoic acid, 4-iodophenylthiourea, and 3-iodotyrosine yield similar fragmentation patterns for a given peptide, although differences in fragment abundance are noted. Iodophenyl isothiocyanate labeling in combination with RDD can be used to differentiate isomeric amino acids within peptides, which should facilitate simplified evaluation of isomers present in complex biological samples.


Assuntos
Iodobenzoatos , Peptídeos , Isotiocianatos , Espectrometria de Massas/métodos , Peptídeos/química
3.
Apoptosis ; 26(3-4): 219-231, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33738673

RESUMO

Acute myeloid leukemia (AML) is a malignant cancer of the hematopoietic system. Although the effectiveness of arsenic compounds has been recognized and applied clinically, some patients are still found resistant to this chemotherapy. In this study, we investigated that a synthetic thyroid hormone analog (TA), 2-iodo-4-nitro-1-(o-tolyloxy) benzene, had a strong apoptosis effect on U937 cells. U937 cells were treated with TA, and examinted the generation of reactive oxygen species (ROS), dysfunction of mitochondria, expression of pro-apoptosis and anti-apoptosis, and cleavage of caspase-3 and Poly (ADP-ribose) polymerase (PARP). Further, it is also evaluated that insight molecular mechanism and signaling pathways involved in the study. It is found that TA significantly induced apoptosis in U937 cells through production of ROS, dysfunction of mitochondria, and activation of caspase cascade. It was also observed that MAPK signaling pathway including ERK, JNK, and P38 signals are involved in the induction of apoptosis. Moreover, marked activation of autophagy and ER stress markers such as LC3, P62, Beclin1 and GRP78, CHOP were observed, respectively. Pretreatment with ER stress inhibitor tauroursodeoxycholic acid (TUDCA) and autophagy inhibitor 3-Methyladenine (3-MA) have successfully attenuated and aggravated TA-induced apoptosis, respectively. We further confirmed the active involvement of ER stress and autophagy signals. In conclusion, TA induced apoptosis through ER stress and activation of autophagy, and the latter is not conducive to TA-induced cell death. Our results may provide a new insight into the strategic development of novel therapy for the treatment of AML.


Assuntos
Apoptose/efeitos dos fármacos , Iodobenzoatos/farmacologia , Leucemia Mieloide/tratamento farmacológico , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Células U937
4.
Phys Chem Chem Phys ; 22(41): 23678-23685, 2020 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-33052992

RESUMO

Solvochromatic effects are most frequently associated with solution-phase phenomena. However, in the gas phase, the absence of solvent leads to intramolecular solvation that can be driven by strong forces including hydrogen bonds and ion-dipole interactions. Here we examine whether isomerization of a single residue in a peptide results in structural changes sufficient to shift the absorption of light by an appended chromophore. By carrying out the experiments inside a mass spectrometer, we can easily monitor photodissociation yield as a readout for chromophore excitation. A series of peptides of different lengths, charge states, and position and identity of the isomerized residue were examined by excitation with both 266 and 213 nm light. The results reveal that differences in intramolecular solvation do lead to solvochromatic shifts in many cases. In addition, the primary product following photoexcitation is a radical. Ion-molecule reactions with this radical and adventitious oxygen were monitored and also found to vary as a function of isomeric state. In this case, differences in intramolecular solvation alter the availability of the reactive radical. Overall, the results reveal that small changes in a single amino acid can influence the overall structural ensemble sufficient to alter the efficiency of multiple gas-phase reactions.


Assuntos
Iodobenzoatos/química , Sondas Moleculares/química , Peptídeos/química , Iodobenzoatos/efeitos da radiação , Isomerismo , Sondas Moleculares/efeitos da radiação , Oxigênio/química , Raios Ultravioleta
5.
Molecules ; 25(20)2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33066684

RESUMO

Efficient treatment of disseminated triple-negative breast cancer (TNBC) remains an unmet clinical need. The epithelial cell adhesion molecule (EpCAM) is often overexpressed on the surface of TNBC cells, which makes EpCAM a potential therapeutic target. Radionuclide molecular imaging of EpCAM expression might permit selection of patients for EpCAM-targeting therapies. In this study, we evaluated a scaffold protein, designed ankyrin repeat protein (DARPin) Ec1, for imaging of EpCAM in TNBC. DARPin Ec1 was labeled with a non-residualizing [125I]I-para-iodobenzoate (PIB) label and a residualizing [99mTc]Tc(CO)3 label. Both imaging probes retained high binding specificity and affinity to EpCAM-expressing MDA-MB-468 TNBC cells after labeling. Internalization studies showed that Ec1 was retained on the surface of MDA-MB-468 cells to a high degree up to 24 h. Biodistribution in Balb/c nu/nu mice bearing MDA-MB-468 xenografts demonstrated specific uptake of both [125I]I-PIB-Ec1 and [99mTc]Tc(CO)3-Ec1 in TNBC tumors. [125I]I-PIB-Ec1 had appreciably lower uptake in normal organs compared with [99mTc]Tc(CO)3-Ec1, which resulted in significantly (p < 0.05) higher tumor-to-organ ratios. The biodistribution data were confirmed by micro-Single-Photon Emission Computed Tomography/Computed Tomography (microSPECT/CT) imaging. In conclusion, an indirectly radioiodinated Ec1 is the preferable probe for imaging of EpCAM in TNBC.


Assuntos
Molécula de Adesão da Célula Epitelial/análise , Imagem Molecular/métodos , Sondas Moleculares/química , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Linhagem Celular Tumoral , Molécula de Adesão da Célula Epitelial/metabolismo , Feminino , Humanos , Radioisótopos do Iodo/química , Radioisótopos do Iodo/farmacocinética , Iodobenzoatos/química , Camundongos Endogâmicos BALB C , Sondas Moleculares/farmacocinética , Proteínas Musculares/química , Proteínas Nucleares/química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Tecnécio , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Chem Asian J ; 15(21): 3551-3557, 2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-32954664

RESUMO

Employing a sequentially activated probe design method, an activatable, switchable and dual-mode probe was designed. This nanoprobe, HSDPP, could be effectively activated by H2 S to form H-type aggregates with green emission; subsequently, the aggregates could bind to mtDNA to form monomers and the emIssion color switched from green to deep-red. We exploited HSDPP to image exogenous and endogenous H2 S in living cells. Of note, for the first time, this novel nanoprobe with an optimal partition coefficient value (LogP=1.269) was successfully applied for tracking the endogenous H2 S upregulation stimulated by cystathionase activator S-adenosyl-L-methionine (SAM) in mice brains. Finally, our work provides an invaluable chemical tool for probing endogenous H2 S upregulation in vitro/vivo and, importantly, affords a prospective design strategy for developing switchable chemosensors to unveil the relationship between biomolecules and DNA in mitochondria in many promising areas.


Assuntos
Encéfalo/metabolismo , Ésteres/química , Corantes Fluorescentes/química , Sulfeto de Hidrogênio/análise , Iodobenzoatos/química , Nanopartículas/química , Animais , Encéfalo/diagnóstico por imagem , Ésteres/síntese química , Corantes Fluorescentes/síntese química , Sulfeto de Hidrogênio/metabolismo , Iodobenzoatos/síntese química , Camundongos , Estrutura Molecular , Imagem Óptica , Tamanho da Partícula , S-Adenosilmetionina/farmacologia , Propriedades de Superfície
7.
Biomed Chromatogr ; 34(10): e4906, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32449534

RESUMO

Tacrine derivatives containing iodobenzoic acid were developed as a novel multitarget-directed ligand and find potential application in the treatment of Alzheimer's disease. The aim of this study is to perform a physicochemical profile of this series. Experimental log P and pKa values were determined and compared with those already calculated. The results indicated better values of the tested compounds than the values predicted using computer software. The stability report was obtained using the developed HPLC method. The stability assay in different environment conditions provided information about the photosensitivity of these compounds and a proper method for the storage of this series of compounds.


Assuntos
Inibidores da Colinesterase , Iodobenzoatos , Tacrina , Doença de Alzheimer , Inibidores da Colinesterase/análise , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Cromatografia Líquida de Alta Pressão , Descoberta de Drogas , Estabilidade de Medicamentos , Humanos , Iodobenzoatos/análise , Iodobenzoatos/química , Iodobenzoatos/metabolismo , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Tacrina/análogos & derivados , Tacrina/análise , Tacrina/química , Tacrina/metabolismo
8.
Anal Chem ; 91(20): 13032-13038, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31498611

RESUMO

Spontaneous chemical modifications play an important role in human disease and aging at the molecular level. Deamidation and isomerization are known to be among the most prevalent chemical modifications in long-lived human proteins and are implicated in a growing list of human pathologies, but the relatively minor chemical change associated with these processes has presented a long standing analytical challenge. Although the adoption of high-resolution mass spectrometry has greatly aided the identification of deamidation sites in proteomic studies, isomerization (and the isomeric products of deamidation) remain exceptionally challenging to characterize. Herein, we present a liquid chromatography/mass spectrometry-based approach for rapidly characterizing the isomeric products of Gln deamidation using diagnostic fragments that are abundantly produced and capable of unambiguously identifying both Glu and isoGlu. Importantly, the informative fragment ions are produced through orthogonal fragmentation pathways, thereby enabling the simultaneous detection of both isomeric forms while retaining compatibility with shotgun proteomics. Furthermore, the diagnostic fragments associated with isoGlu pinpoint the location of the modified residue. The utility of this technique is demonstrated by characterizing the isomeric products generated during in vitro aging of a series of glutamine-containing peptides. Sequence-dependent product profiles are obtained, and the abundance of deamidation-linked racemization is examined. Finally, comparisons are made between Gln deamidation, which is relatively poorly understood, and asparagine deamidation, which has been more thoroughly studied.


Assuntos
Cristalinas/análise , Glutamina/análogos & derivados , Glutamina/análise , Cromatografia Líquida , Cristalinas/química , Cristalinas/metabolismo , Glutamina/metabolismo , Humanos , Hidrólise , Iodobenzoatos/química , Cinética , Cristalino/química , Espectrometria de Massas , Fatores de Tempo
9.
Mol Cell Biochem ; 460(1-2): 123-150, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31313023

RESUMO

A series of nine tetrahydroacridine derivatives with iodobenzoic moiety were synthesized and evaluated for their cytotoxic activity against cancer cell lines-A549 (human lung adenocarcinoma), HT-29 (human colorectal adenocarcinoma) and somatic cell line-EA.hy926 (human umbilical vein cell line). All compounds displayed high cytotoxicity activity against A549 (IC50 59.12-14.87 µM) and HT-29 (IC50 17.32-5.90 µM) cell lines, higher than control agents-etoposide and 5-fluorouracil. Structure-activity relationship showed that the position of iodine in the substituent in the para position and longer linker most strongly enhanced the cytotoxic effect. Among derivatives, 1i turned out to be the most cytotoxic and displayed IC50 values of 14.87 µM against A549 and 5.90 µM against HT-29 cell lines. In hyaluronidase inhibition assay, all compounds presented anti-inflammatory activity, however, slightly lower than reference compound. ADMET prediction showed that almost all compounds had good pharmacokinetic profiles. 1b, 1c and 1f compounds turned out to act against chemoresistance in cisplatin-resistant 253J B-V cells. Compounds intercalated into DNA and inhibited cell cycle in G0/G1 phase-the strongest inhibition was observed for 1i in A549 and 1c in HT-29. Among compounds, the highest apoptotic effect in both cell lines was observed after treatment with 1i. Compounds caused DNA damage and H2AX phosphorylation, which was detected in A549 and HT-29 cells. All research confirmed anticancer properties of novel tetrahydroacridine derivatives and explained a few pathways of their mechanism of cytotoxic action.


Assuntos
Aminacrina/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Colorretais/patologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Iodobenzoatos/farmacologia , Neoplasias Pulmonares/patologia , Células A549 , Aminacrina/química , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Citoproteção/efeitos dos fármacos , DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células HT29 , Histonas/metabolismo , Humanos , Hialuronoglucosaminidase/metabolismo , Concentração Inibidora 50 , Mutagênicos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/metabolismo , Ensaio Tumoral de Célula-Tronco
10.
Int J Mol Sci ; 20(12)2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31234471

RESUMO

Radionuclide molecular imaging of human epidermal growth factor receptor 2 (HER2) in breast and gastroesophageal cancer might be used to stratify patients for HER2-targeted therapy as well as monitor treatment response and disease progression. Designed ankyrin repeat proteins (DARPins) are small engineered scaffold proteins with favorable properties for molecular imaging. Herein we compared two methods for labeling the anti-HER2 DARPin (HE)3-G3, direct and indirect radioiodination. We hypothesized that the use of N-succinimidyl-para-iodobenzoate (SPIB) for radioiodination would facilitate the clearance of radiometabolites and improve the contrast of imaging. Both radiolabeled (HE)3-G3 variants preserved their binding specificity and high affinity to HER2-expressing cells. The specificity of tumor targeting in vivo was also demonstrated. A biodistribution comparison of [125I]I-(HE)3-G3 and [125I]I-PIB-(HE)3-G3, in mice bearing HER2 expressing SKOV3 xenografts, showed rapid clearance of [125I]I-PIB-(HE)3-G3 from normal organs and tissues and low accumulation of activity in organs with NaI-symporter expression. Both radiolabeled (HE)3-G3 variants had equal tumor uptake. Consequently, the indirect label provided higher tumor-to-blood and tumor-to-organ ratios compared with the direct label. Comparative Single Photon Emission Computed Tomography (SPECT)/CT imaging of HER2 expression in SKOV3 xenografts, using both radiolabeled DARPins, demonstrated the superior imaging contrast of the indirect label. Indirect radioiodination of (HE)3-G3 using SPIB could be further applied for SPECT and PET imaging with iodine-123 and iodine-124.


Assuntos
Repetição de Anquirina , Radioisótopos do Iodo/análise , Iodobenzoatos/análise , Neoplasias Ovarianas/diagnóstico por imagem , Receptor ErbB-2/análise , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Imagem Molecular/métodos , Tomografia Computadorizada de Emissão de Fóton Único/métodos
11.
Acta Crystallogr C Struct Chem ; 74(Pt 7): 839-846, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29973423

RESUMO

The syntheses of nine new 5-iodosalicylic acid-based 1,3,4-oxadiazoline derivatives starting from methyl salicylate are described. These compounds are 2-[4-acetyl-5-methyl-5-(3-nitrophenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate (6a), 2-[4-acetyl-5-methyl-5-(4-nitrophenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate (6b), 2-(4-acetyl-5-methyl-5-phenyl-4,5-dihydro-1,3,4-oxadiazol-2-yl)-4-iodophenyl acetate, C19H17IN2O4 (6c), 2-[4-acetyl-5-(4-fluorophenyl)-5-methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate, C19H16FIN2O4 (6d), 2-[4-acetyl-5-(4-chlorophenyl)-5-methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate, C19H16ClIN2O4 (6e), 2-[4-acetyl-5-(3-bromophenyl)-5-methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate (6f), 2-[4-acetyl-5-(4-bromophenyl)-5-methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate (6g), 2-[4-acetyl-5-methyl-5-(4-methylphenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate (6h) and 2-[5-(4-acetamidophenyl)-4-acetyl-5-methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate (6i). The compounds were characterized by mass, 1H NMR and 13C NMR spectroscopies. Single-crystal X-ray diffraction studies were also carried out for 6c, 6d and 6e. Compounds 6c and 6d are isomorphous, with the 1,3,4-oxadiazoline ring having an envelope conformation, where the disubstituted C atom is the flap. The packing is determined by C-H...O, C-H...π and I...π interactions. For 6e, the 1,3,4-oxadiazoline ring is almost planar. In the packing, Cl...π interactions are observed, while the I atom is not involved in short interactions. Compounds 6d, 6e, 6f and 6h show good inhibiting abilities on the human cancer cell lines KB and Hep-G2, with IC50 values of 0.9-4.5 µM.


Assuntos
Iodobenzoatos/síntese química , Iodobenzoatos/toxicidade , Cristalografia por Raios X , Humanos , Ligação de Hidrogênio , Iodobenzoatos/química
12.
Chem Biol Drug Des ; 91(2): 505-518, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28944565

RESUMO

New synthesized series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with iodobenzoic acid moiety were studied for their inhibitory activity toward cholinesterase and against ß-amyloid aggregation. All novel molecules 3a-3i interacted with both cholinesterases-acetylcholinesterase and butyrylcholinesterase-delivered nanomolar IC50 values. The structure-activity relationship showed that N-butyl moiety derivatives are stronger inhibitors toward AChE and BuChE than N-ethyl and N-propyl moieties compounds. The most potent compound toward acetylcholinesterase was inhibitor 3f (IC50  = 31.2 nm), and it was more active than reference drug, tacrine (IC50  = 100.2 nm). Compound 3f showed strong inhibition of butyrylcholinesterase (IC50  = 8.0 nm), also higher than tacrine (IC50  = 16.3 nm). In the kinetic studies, compound 3f revealed mixed type of acetylcholinesterase inhibition. The computer modeling was carried out. The most active compound 3f was confirmed as peripheral anionic site inhibitor of acetylcholinesterase. Moreover, molecule 3f inhibited ß-amyloid aggregation (at the concentration 10 µm-24.96% of inhibition, 25 µm-72%, 50 µm-78.44%, and 100 µm-84.92%). Therefore, among all examined, compound 3f is the most promising molecule for further, more detailed research of novel multifunctional agents in the therapy of Alzheimer's disease.


Assuntos
Acetilcolinesterase/química , Acridinas/química , Butirilcolinesterase/química , Inibidores da Colinesterase/química , Iodobenzoatos/química , Acetilcolinesterase/metabolismo , Acridinas/metabolismo , Peptídeos beta-Amiloides/metabolismo , Sítios de Ligação , Butirilcolinesterase/metabolismo , Domínio Catalítico , Inibidores da Colinesterase/metabolismo , Humanos , Concentração Inibidora 50 , Cinética , Simulação de Acoplamento Molecular , Fragmentos de Peptídeos/metabolismo , Relação Estrutura-Atividade
13.
Acta Crystallogr D Struct Biol ; 73(Pt 11): 896-909, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29095162

RESUMO

Serum albumin (SA) is the most abundant protein in plasma and is the main transporter of molecules in the circulatory system of all vertebrates, with applications in medicine, the pharmaceutical industry and molecular biology. It is known that albumins from different organisms vary in sequence; thus, it is important to know the impact of the amino-acid sequence on the three-dimensional structure and ligand-binding properties. Here, crystal structures of ovine (OSA) and caprine (CSA) serum albumins, isolated from sheep and goat blood, are described, as well those of their complexes with 3,5-diiodosalicylic acid (DIS): OSA-DIS (2.20 Šresolution) and CSA-DIS (1.78 Šresolution). The ligand-free OSA structure was determined in the trigonal space group P3221 at 2.30 Šresolution, while that of CSA in the orthorhombic space group P212121 was determined at 1.94 Šresolution. Both albumins are also capable of crystallizing in the triclinic space group P1, giving isostructural crystals that diffract to around 2.5 Šresolution. A comparison of OSA and CSA with the closely related bovine serum albumin (BSA) shows both similarities and differences in the distribution of DIS binding sites. The investigated serum albumins from domesticated ruminants in their complexes with DIS are also compared with the analogous structures of equine and human serum albumins (ESA-DIS and HSA-DIS). Surprisingly, despite 98% sequence similarity, OSA binds only two molecules of DIS, whereas CSA binds six molecules of this ligand. Moreover, the binding of DIS to OSA and CSA introduced changes in the overall architecture of the proteins, causing not only different conformations of the amino-acid side chains in the binding pockets, but also a significant shift of the whole helices, changing the volume of the binding cavities.


Assuntos
Iodobenzoatos/química , Iodobenzoatos/metabolismo , Salicilatos/química , Salicilatos/metabolismo , Albumina Sérica/química , Albumina Sérica/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação , Domínio Catalítico , Bovinos , Cristalização , Cristalografia por Raios X , Cavalos , Humanos , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Ruminantes , Homologia de Sequência , Ovinos
14.
J Nat Prod ; 80(5): 1648-1657, 2017 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-28497968

RESUMO

A chemoenzymatic synthesis of a small library of dimeric neolignans inspired by magnolol (1) is reported. The 2-iodoxybenzoic acid (IBX)-mediated regioselective ortho-hydroxylation of magnolol is described, affording the bisphenols 6 and 7. Further magnolol analogues (12, 13, 15-17, 19-23) were obtained from eugenol (3), tyrosol (4), and homovanillic alcohol (5), through horseradish peroxidase (HRP)-mediated oxidative coupling and regioselective ortho-hydroxylation or ortho-demethylation in the presence of IBX, followed by reductive treatment with Na2S2O4. A chemoselective protection/deprotection of the alcoholic group of 4 and 5 was carried out by lipase-mediated acetylation/deacetylation. The dimeric neolignans, together with 1 and honokiol (2), were evaluated as inhibitors of yeast α-glucosidase, in view of their possible utilization and optimization as antidiabetic drugs. The synthetic analogues of magnolol showed a strong inhibitory activity with IC50 values in the range 0.15-4.1 µM, much lower than those of honokiol and the reference compounds quercetin and acarbose. In particular, a very potent inhibitory activity, with an IC50 of 0.15 µM, was observed for 1,1'-dityrosol-8,8'-diacetate (15), and comparable inhibitory activities were also shown by bisphenols 6 (0.49 µM), 13 (0.50 µM), and 22 (0.86 µM). A kinetic study showed that 15 acts as a competitive inhibitor, with a Ki value of 0.86 µM.


Assuntos
Compostos de Bifenilo/isolamento & purificação , Compostos de Bifenilo/farmacologia , Eugenol/química , Hipoglicemiantes/farmacocinética , Iodobenzoatos/química , Lignanas/síntese química , Lignanas/isolamento & purificação , Lignanas/farmacologia , Álcool Feniletílico/análogos & derivados , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo , Compostos de Bifenilo/química , Eugenol/farmacologia , Hipoglicemiantes/química , Iodobenzenos , Iodobenzoatos/farmacocinética , Lignanas/química , Estrutura Molecular , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia
15.
Plant Physiol ; 172(1): 198-220, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27485881

RESUMO

Plant secondary-thickened cell walls are characterized by the presence of lignin, a recalcitrant and hydrophobic polymer that provides mechanical strength and ensures long-distance water transport. Exactly the recalcitrance and hydrophobicity of lignin put a burden on the industrial processing efficiency of lignocellulosic biomass. Both forward and reverse genetic strategies have been used intensively to unravel the molecular mechanism of lignin deposition. As an alternative strategy, we introduce here a forward chemical genetic approach to find candidate inhibitors of lignification. A high-throughput assay to assess lignification in Arabidopsis (Arabidopsis thaliana) seedlings was developed and used to screen a 10-k library of structurally diverse, synthetic molecules. Of the 73 compounds that reduced lignin deposition, 39 that had a major impact were retained and classified into five clusters based on the shift they induced in the phenolic profile of Arabidopsis seedlings. One representative compound of each cluster was selected for further lignin-specific assays, leading to the identification of an aromatic compound that is processed in the plant into two fragments, both having inhibitory activity against lignification. One fragment, p-iodobenzoic acid, was further characterized as a new inhibitor of CINNAMATE 4-HYDROXYLASE, a key enzyme of the phenylpropanoid pathway synthesizing the building blocks of the lignin polymer. As such, we provide proof of concept of this chemical biology approach to screen for inhibitors of lignification and present a broad array of putative inhibitors of lignin deposition for further characterization.


Assuntos
Arabidopsis/metabolismo , Iodobenzoatos/farmacologia , Lignina/metabolismo , Transcinamato 4-Mono-Oxigenase/antagonistas & inibidores , Arabidopsis/citologia , Arabidopsis/genética , Vias Biossintéticas/efeitos dos fármacos , Vias Biossintéticas/genética , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , Análise por Conglomerados , Inibidores Enzimáticos/química , Inibidores Enzimáticos/classificação , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Ensaios de Triagem em Larga Escala/métodos , Iodobenzoatos/química , Espectrometria de Massas , Estrutura Molecular , Propanóis/metabolismo , Plântula/enzimologia , Plântula/genética , Plântula/metabolismo , Transcinamato 4-Mono-Oxigenase/genética , Transcinamato 4-Mono-Oxigenase/metabolismo
16.
ACS Comb Sci ; 18(10): 625-629, 2016 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-27571034

RESUMO

DNA-encoded library technology (ELT) is a powerful tool for the discovery of new small-molecule ligands to various protein targets. Here we report the design and synthesis of biaryl DNA-encoded libraries based on the scaffold of 5-formyl 3-iodobenzoic acid. Three reactions on DNA template, acylation, Suzuki-Miyaura coupling and reductive amination, were applied in the library synthesis. The three cycle library of 3.5 million diversity has delivered potent hits for phosphoinositide 3-kinase α (PI3Kα).


Assuntos
DNA/química , Iodobenzoatos/química , Fosfatidilinositol 3-Quinases/química , Bibliotecas de Moléculas Pequenas/síntese química , Acilação , Aminação , Técnicas de Química Combinatória , Humanos , Ligantes , Relação Estrutura-Atividade
17.
Appl Radiat Isot ; 108: 116-123, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26720260

RESUMO

This study was aimed to evaluate the effect of (124)I-labeling with hexadecyl-4-iodobenzoate (HIB) on gene expression related to cell cycle, DNA repair, transcription, proliferation and differentiation of adipose-derived stem cells (ADSCs). [(124)I]HIB showed high labeling efficiency with ADSCs (51.3±1.3%, 0.3-2.0 Bq/cell) and there is no morphological change of ADSCs. In the microarray analysis of gene expression pattern, differences were not observed between non-labeled and [(124)I]HIB-labeled ADSCs. We demonstrated that (124)I-labeling with HIB did not affect the biological properties of ADSCs.


Assuntos
Rastreamento de Células/métodos , Iodobenzoatos/efeitos adversos , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/terapia , Transplante de Células-Tronco/métodos , Células-Tronco/diagnóstico por imagem , Adipócitos/diagnóstico por imagem , Adipócitos/efeitos dos fármacos , Adipócitos/transplante , Animais , Células Cultivadas , Radioisótopos do Iodo/efeitos adversos , Marcação por Isótopo/métodos , Masculino , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/efeitos adversos , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Transplante de Células-Tronco/efeitos adversos , Células-Tronco/efeitos dos fármacos , Resultado do Tratamento
18.
Environ Int ; 86: 107-18, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26571428

RESUMO

This work analyses the presence of forty-eight emerging pollutants, including twenty-five drugs of abuse and metabolites, seventeen cytostatic drugs and six iodinated contrast media, in tap water from the Madrid Region. Analysis of the target compounds in the tap water was performed by means of (on-line or off-line) solid-phase extraction followed by analysis by liquid chromatography-tandem mass spectrometry. A preliminary human health risk characterization was undertaken for each individual compound and for different groups of compounds with a common mechanism of action found in tap water. The results of the study showed the presence of eight out of the twenty-five drugs of abuse and metabolites analysed, namely, the cocainics cocaine and benzoylecgonine, the amphetamine-type stimulants ephedrine, 3,4-methylenedioxymethamphetamine and methamphetamine, the opioid methadone and its metabolite 2-ethylene-1,5-dimethyl-3,3-diphenylpyrrolidine and, finally caffeine at concentrations ranging from 0.11 to 502 ng L(-1). Four out of the six analysed iodinated contrast media, namely, diatrizoate, iohexol, iomeprol and iopromide, were detected in at least one sample, with concentration values varying between 0.4 and 5 ng L(-1). Cytostatic compounds were not detected in any sample. Caffeine was the substance showing the highest concentrations, up to 502 ng L(-1), mainly in the drinking water sampling point located in Madrid city. Among the other drugs of abuse, the most abundant compounds were cocaine and benzoylecgonine, detected at concentrations ranging from 0.11 to 86 ng L(-1) and from 0.11 to 53 ng L(-1), respectively. Regarding iodinated contrast media, iohexol was the most ubiquitous and abundant compound, with a frequency of detection of 100% and concentrations from 0.5 to 5.0 ng L(-1) in basically the same range in all sampling points. Taking into account the results and types of treatment applied, ozonisation plus granular activated carbon filtration appears to be efficient in the removal of cocaine and benzoylecgonine. For the amphetamine-type stimulants, opioids and caffeine, ozonisation plus granular activated carbon filtration and ultrafiltration plus reverse osmosis showed higher removal efficiency than sand filtration. The human health risk characterization performed indicates that the lifetime consumption of the tap waters analysed has associated a negligible human health concern.


Assuntos
Meios de Contraste/análise , Citostáticos/análise , Água Potável/análise , Monitoramento Ambiental/métodos , Drogas Ilícitas/análise , Iodobenzoatos/análise , Poluentes Químicos da Água/análise , Cromatografia Líquida , Água Potável/normas , Humanos , Espectrometria de Massas , Saúde Pública , Medição de Risco , Extração em Fase Sólida , Espanha , Purificação da Água/métodos
19.
Rapid Commun Mass Spectrom ; 29(4): 322-6, 2015 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-26406343

RESUMO

RATIONALE: One of the major shortcomings of linear ion trap mass spectrometers is poor resolution. Failure to resolve isotopic peaks makes charge state determination for large proteins very difficult, hindering the ability to perform top-down proteomics. METHODS: Peptides, proteins and corresponding fragments modified with para-iodobenzoate were trapped and irradiated with 266 nm light from an Nd:YAG laser. Loss of iodine due to photodissociation was then used to assign charge states by measuring the corresponding m/z shifts. RESULTS: Initial experiments on small peptides illustrate the feasibility of the method. Further studies performed on larger proteins in higher charge states yielded similar results, revealing that fragment ions over a significant mass range either remain in or are quickly cooled to the laser overlap region of the ion trap. CONCLUSIONS: Rapid charge state assignment for both whole molecules and collision-induced dissociation (CID) fragments can be obtained by photoactivation of chromophores with labile carbon-iodine bonds.


Assuntos
Citocromos c/química , Mioglobina/química , Peptídeos/química , Sequência de Aminoácidos , Animais , Halogenação , Cavalos , Iodobenzoatos/química , Espectrometria de Massas/métodos , Fotólise , Eletricidade Estática
20.
Angew Chem Int Ed Engl ; 54(46): 13719-23, 2015 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-26381547

RESUMO

A new class of hypervalent iodine reagents containing phthalimidate was synthesized, and structurally characterized by X-ray analysis. The benziodoxole-based reagent displays satisfactory solubility in common organic solvents and is reasonably stable in solution as well as in the solid state. The reagent was used for the oxidative amination of the C(sp(3))-H bond of N,N-dimethylanilines. In addition, the reagent was also applicable to oxidative amination with rearrangement of trialkylamines as well as enamines that were prepared in situ from secondary amines and aldehydes.


Assuntos
Aminas/síntese química , Iodo/química , Iodobenzoatos/química , Ftalimidas/química , Aldeídos/síntese química , Aldeídos/química , Aminação , Aminas/química , Iodobenzenos , Iodobenzoatos/síntese química , Modelos Moleculares , Estrutura Molecular , Oxirredução
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