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1.
J Cell Biochem ; 118(5): 1164-1173, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27684057

RESUMO

9-[(3-chloro)phenylamine]-2-[3-(diethylamine)propylamine]thiazolo[5,4-b]quinolone (D3ClP) is a bioisostere of N-(4-(acridin-9-ylamino)-3-methoxyphenyl)methanesulfonamide (m-AMSA) a DNA topoisomerase II inhibitor with proven cytotoxic activity and known to induce DNA damage and apoptotic cell death in K562 cells. However, recent evidence is not consistent with DNA topoisomerase II (DNA TOP2) as the primary target of D3ClP, in contrast to m-AMSA. We provide evidence of histone γH2AX phosphorylation at Ser135 in HeLa cells treated with D3ClP, a marker of DNA double strand repair through Mre11-Rad50-Nbs1 (MRN) pathway. Using two-dimensional gel electrophoresis and mass spectrometry, the upregulation of the protein GRP78, the cleavage of Cytokeratin 18, and the downregulation of prothymosine, calumenin, and the α chain of the nascent polypeptide associated complex were observed in HeLa cells treated with D3ClP. An increase in GRP78 has been related with the onset and progression of the unfolded protein response (UPR), a process aimed to reduce endoplasmic reticulum (ER) stress and protein misfolding. The IRE1-α dependent splicing of mRNA encoding X-box binding protein 1 was detected. Microtubule-associated Proteins 1A/1B, Light Chain 3-II (LC3b-II) accumulation was observed, and suggest some involvement of autophagy. The production of the pro-apoptotic protein DNA-damage-inducible protein 153 (GADD-153) was also detected. These results, are consistent with the induction of the UPR and the DNA-Damage Response in D3ClP-treated HeLa cells, and are also consistent with a concurrent apoptotic cell death. J. Cell. Biochem. 118: 1164-1173, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Aminoquinolinas/farmacologia , Dano ao DNA , Proteômica/métodos , Tiazóis/farmacologia , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Retículo Endoplasmático/efeitos dos fármacos , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células HeLa , Histonas/metabolismo , Humanos , Fosforilação , Proteoma/efeitos dos fármacos , Serina/metabolismo , Fator de Transcrição CHOP/metabolismo
2.
Acta Crystallogr Sect E Struct Rep Online ; 70(Pt 9): o930-1, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-25309260

RESUMO

The mol-ecular conformation of the title compound, C14H18N2O3S2, is stabilized by intra-molecular N-H⋯N and C-H⋯O hydrogen bonds. The crystal packing is characterized by a series of C-H⋯O hydrogen bonds, resulting in a three-dimensional network.

3.
Biochem J ; 439(3): 443-52, 2011 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-21732915

RESUMO

PaBADH (Pseudomonas aeruginosa betaine aldehyde dehydrogenase) catalyses the irreversible NAD(P)+-dependent oxidation of betaine aldehyde to its corresponding acid, the osmoprotector glycine betaine. This reaction is involved in the catabolism of choline and in the response of this important pathogen to the osmotic and oxidative stresses prevalent in infection sites. The crystal structure of PaBADH in complex with NADPH showed a novel covalent adduct between the C2N of the pyridine ring and the sulfur atom of the catalytic cysteine residue, Cys286. This kind of adduct has not been reported previously either for a cysteine residue or for a low-molecular-mass thiol. The Michael addition of the cysteine thiolate in the 'resting' conformation to the double bond of the α,ß-unsaturated nicotinamide is facilitated by the particular conformation of NADPH in the active site of PaBADH (also observed in the crystal structure of the Cys286Ala mutant) and by an ordered water molecule hydrogen bonded to the carboxamide group. Reversible formation of NAD(P)H-Cys286 adducts in solution causes reversible enzyme inactivation as well as the loss of Cys286 reactivity towards thiol-specific reagents. This novel covalent modification may provide a physiologically relevant regulatory mechanism of the irreversible PaBADH-catalysed reaction, preventing deleterious decreases in the intracellular NAD(P)+/NAD(P)H ratios.


Assuntos
Proteínas de Bactérias/química , Betaína-Aldeído Desidrogenase/química , Cisteína/química , Adutos de DNA/química , NADP/química , Pseudomonas aeruginosa/enzimologia , Aldeído Desidrogenase/química , Aldeído Desidrogenase/genética , Proteínas de Bactérias/genética , Betaína-Aldeído Desidrogenase/genética , Domínio Catalítico/genética , Cristalografia por Raios X , Cisteína/genética , Adutos de DNA/genética , NADP/metabolismo , Pseudomonas aeruginosa/genética
4.
Bioorg Med Chem ; 17(9): 3266-77, 2009 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-19364657

RESUMO

Some novel 9-anilinothiazolo[5,4-b]quinoline derivatives were synthesized and their cytotoxic activities were examined. The inhibition of some of the most active compounds over human topoisomerase II (Topo II) activity was assessed with the kDNA decatenation assay. The novel compounds differ in the substituents attached to the anilino ring, a dialkylamino alkylamino group, a saturated heterocyclic moiety, a methylthio group at position 2 and a fluorine atom present or absent at 7-position. According to the data, compounds with a diethylaminopropylamino group and a chlorine atom at 4'-position of the anilino ring were the most cytotoxic. The molecular models of all compounds indicated a correlation between hydrophobicity and cytotoxic activity although the direction and magnitude of the dipole moment also had a significant influence on its cytotoxicity. The 2-dialkylaminoalkylamino substituent is flexible and is known to facilitate the crossing of cell membranes; thus, this last barrier may be a limiting step in the mechanisms mediating the cytotoxicity. On the other hand, the activity of 2-methylthio derivatives seems to rely more on the electronic effects brought about by the substitution of the aniline ring. The synthesis, cytotoxicity against cancer cell lines, in vitro inhibition of human topoisomerase II, molecular modeling and the preliminary analysis of structure-activity relationships are presented.


Assuntos
Compostos de Anilina/química , Compostos de Anilina/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Inibidores da Topoisomerase II , Compostos de Anilina/síntese química , DNA/genética , DNA/metabolismo , DNA Topoisomerases Tipo II/química , DNA Topoisomerases Tipo II/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Células K562 , Modelos Moleculares , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Quinolinas/síntese química , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologia
5.
Bioorg Med Chem ; 16(3): 1142-9, 2008 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-18035542

RESUMO

A series of novel alkylamino and 9-anilinothiazolo[5,4-b]quinolines were synthesized as potential antitumoral agents. The in vitro cytotoxicity of these compounds was evaluated on several cell lines. The inclusion of electron-withdrawn/acceptor hydrogen-bond groups at position 3' of the anilino ring and the presence of an alkylamino chain on the tricyclic framework (regardless of its position) seem to be structural features relevant to cytotoxic activity.


Assuntos
DNA/genética , Quinolinas/síntese química , Quinolinas/toxicidade , Tiazóis/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Quinolinas/química , Relação Estrutura-Atividade
6.
Eur J Med Chem ; 37(12): 945-51, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12660019

RESUMO

In order to analyse the relevance of the indole electronic region in the binding of melatonin to its receptors, we prepared several analogues with p-H, p-NO(2), p-MeO, p-F and p-Me of benzyl, benzoyl and phenyl substituents at position 1 of the melatonin skeleton. The electronic properties of the analogues, as calculated with the semiempirical method AM1, were correlated with their affinity for the melatonin receptor from chicken brain membranes. Different trends were observed for each compound series. Compound 5c, with a p-NO(2)-benzoyl group, showed the best affinity indicating the importance of a polar bulky group in the receptor interaction.


Assuntos
Melatonina/análogos & derivados , Melatonina/metabolismo , Receptores de Melatonina/metabolismo , Animais , Encéfalo/metabolismo , Galinhas , Cinética , Espectroscopia de Ressonância Magnética , Melatonina/química , Modelos Moleculares , Conformação Molecular , Estrutura Molecular
7.
Eur J Med Chem ; 39(1): 5-10, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14987829

RESUMO

Five new 9-anilinothiazolo[5,4-b]quinoline derivatives (compounds 5, 7, 9, 10, 11) have been prepared. Some of the compounds were prepared by coupling properly substituted anilines to the novel compound 9-chloro-2-(methylthio)thiazolo[5,4-b]quinoline. Of these, compound 7 (9-anilino-2-[[2-(N,N-diethylamino)ethyl]amino]thiazolo[5,4-b]quinoline) showed the best cytotoxic activity in several cell lines. All compounds demonstrated DNA binding in nanomolar range. Compound 7 inhibited the (14)C-thymidine incorporation into DNA. Results indicate that these derivatives deserve more considerations as potential antitumoral drugs.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Animais , Células CHO , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cricetinae , DNA/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/farmacologia , Células K562 , Estrutura Molecular , Relação Estrutura-Atividade
8.
Behav Brain Res ; 236(1): 148-156, 2013 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-22960257

RESUMO

Melatonin has been mainly used for alleviating some disorders related with insomnia and circadian rhythmicity. The use of this hormone has been limited, among others, due to its short half-life and instability. This study reports some behavioural actions of two new melatonin analogues that incorporate a phenyl or a benzoyl group at the nitrogen atom of the melatonin molecule. Although diazepam was about 10 times more potent than either of the melatonin analogues, results show that in general these last display better anxiolytic, anticonvulsant and sedative actions than the original molecule.


Assuntos
Antioxidantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Melatonina/análogos & derivados , Melatonina/farmacologia , Animais , Ansiolíticos/farmacologia , Anticonvulsivantes/farmacologia , Ansiedade/psicologia , Diazepam/farmacologia , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Equilíbrio Postural/efeitos dos fármacos , Convulsões/induzido quimicamente , Convulsões/prevenção & controle
9.
Anticancer Res ; 32(12): 5159-65, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23225412

RESUMO

BACKGROUND: D3CLP (9-[(3-chloro)phenylamine]-2-[3-(diethylamine)propylamine]thiazolo[5,4-b]quinoline) is a potent cytotoxic thiazolo[5,4-b]quinoline synthetic derivative that induces apoptosis of leukemia cells, while it displays low toxicity towards non-tumoral cells. The aim of this study was to determine if D3CLP can enhance the cytotoxicity of other antineoplastic drugs. MATERIALS AND METHODS: Leukemia, breast and cervical cancer cell lines were exposed to D3CLP-alone or in combination with imatinib, tamoxifen or cisplatin, respectively. Cell viability after treatment was evaluated by the MTT assay, and cell death by the TUNEL assay. The effects of combined treatments were analyzed by combination index and isobolographic analysis. RESULTS: Antiproliferative activity results indicate that D3CLP in combination with antineoplastic drugs induced a synergistic effect, at 3:1 and 1:1 ratios for D3CLP plus imatinib in K-562 leukemia cells, and at a 3:1 ratio for D3CLP with cisplatin in HeLa cells, as determined by their combination index. Furthermore, isobolographic analysis demonstrated a significant synergism for a 3:1 combination ratio of D3CLP with cisplatin in HeLa cells. In addition, TUNEL assay suggests cell death by apoptosis of HeLa cells after treatment with D3CLP and its combination with cisplatin at a 3:1 ratio. CONCLUSION: Overall the results indicate that D3CLP, in combined preparation with antineoplastic drugs, is a good candidate for pre-clinical studies in the treatment of different carcinoma cell types.


Assuntos
Aminoquinolinas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cisplatino/farmacologia , Tiazóis/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Aminoquinolinas/administração & dosagem , Benzamidas , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/administração & dosagem , Fragmentação do DNA/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Feminino , Células HeLa , Humanos , Mesilato de Imatinib , Células K562 , Células MCF-7 , Piperazinas/administração & dosagem , Piperazinas/farmacologia , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Tamoxifeno/administração & dosagem , Tamoxifeno/farmacologia , Tiazóis/administração & dosagem , Neoplasias do Colo do Útero/patologia
10.
J Phys Chem B ; 115(45): 13408-17, 2011 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-21995683

RESUMO

S-Allylcysteine (SAC) is the most abundant compound in aged garlic extracts, and its antioxidant properties have been demonstrated. It is known that SAC is able to scavenge different reactive species including hydroxyl radical (•OH), although its potential ability to scavenge peroxyl radical (ROO•) has not been explored. In this work the ability of SAC to scavenge ROO• was evaluated, as well as the role of the allyl group (-S-CH(2)-CH═CH(2)) in its free radical scavenging activity. Two derived compounds of SAC were prepared: S-benzylcysteine (SBC) and S-propylcysteine (SPC). Their abilities to scavenge •OH and ROO• were measured. A computational analysis was performed to elucidate the mechanism by which these compounds scavenge •OH and ROO•. SAC was able to scavenge •OH and ROO•, in a concentration-dependent way. Such activity was significantly ameliorated when the allyl group was replaced by benzyl or propyl groups. It was shown for the first time that SAC is able to scavenge ROO•.


Assuntos
Cisteína/análogos & derivados , Sequestradores de Radicais Livres/química , Radical Hidroxila/química , Peróxidos/química , Cisteína/química , Teoria Quântica , Termodinâmica
11.
Eur J Med Chem ; 46(6): 2102-8, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21420205

RESUMO

Thiazolo[5,4-b]quinolines are compounds structurally related to m-Amsacrine (m-Amsa), a potent antileukemic drug that intercalates to DNA and inhibits topoisomerase II in vitro inducing cell death. The clinical use of m-Amsa and other neoplastic drugs is limited due to side effects and drug resistance. In the present study we evaluated one thiazolo[5,4-b]quinoline derivate, 9-[(3-chloro)phenylamine]-2-[3-(diethylamine)propylamine]thiazolo[5,4-b]quinoline (D3CLP), considered isosteric with 9-anilinoacridines, in order to determine its relative cytotoxic activity in tumoral versus non-tumoral cells, as well as the cell death mechanism induced by D3CLP on K-562 human leukemia cells. D3CLP was found to be four times more cytotoxic to tumor cells than Peripheral Blood Monocyte Cells (PBMCs). On the other hand, D3CLP induces cell death without previous cell cycle arrest at any phase, as shown by flow cytometry after 12 h of exposure to this compound. Interestingly, we detected a subdiploid peak 24 h after treatment. Signs of apoptosis were evident, as detected by TUNEL positive cells, chromatin condensation and nuclear fragmentation. Effector caspases activation were assessed with peak activity at 24 h after treatment (as detected by fluorometry assays), at which time a subdiploid peak was found in flow cytometry histograms. All data are consistent with the induction of apoptotic cell death in K-562 cells via effector caspases activation. In conclusion, the significant cytotoxicity of D3CLP together with the cell death type it produces, justifies further experimental and preclinical evaluation of this compound in the effort to find new and highly specific anti-tumor agents against leukemia cells.


Assuntos
Aminoquinolinas/farmacologia , Antineoplásicos/farmacologia , Inibidores de Caspase , Inibidores de Cisteína Proteinase/farmacologia , Tiazóis/farmacologia , Aminoquinolinas/síntese química , Aminoquinolinas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ativação Enzimática/efeitos dos fármacos , Humanos , Células K562 , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Células Tumorais Cultivadas
12.
J Mol Graph Model ; 27(8): 900-7, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19269869

RESUMO

Although 9-anilinoacridines are among the best studied antitumoral intercalators, there are few studies about the effect of isosteric substitution of a benzene moiety for a heterocycle ring in the acridine framework. According to these studies, this approach may lead to effective cytotoxic agents, but good cytotoxic activity depends on structural requirements in the aniline ring which differ from those in 9-anilinoacridines. The present paper deals with molecular modeling studies of some 9-anilino substituted tricyclic compounds and their intercalation complexes (in various DNA sequences) resulting from docking the compounds into various DNA sequences. As expected, the isosteric substitution in 9-anilinoacridines influences the LUMO energy values and orbital distribution, the dipole moment, electrostatic charges and the conformation of the anilino ring. Other important differences are observed during the docking studies, for example, changes in the spatial arrangement of the tricyclic nucleus and the anilino ring at the intercalation site. Semiempirical calculations of the intercalation complexes show that the isosteric replacement of a benzene ring in the acridine nucleus affects not only DNA affinity but also base pair selectivity. These findings explain, at least partially, the different structural requirements observed in several 9-anilino substituted tricyclic compounds for cytotoxic activity. Thus, the data presented here may guide the rational design of new agents with different DNA binding properties and/or a cytotoxic profile by isosteric substitution of known intercalators.


Assuntos
DNA/química , Compostos Heterocíclicos com 3 Anéis/química , Substâncias Intercalantes/química , Acridinas/química , Simulação por Computador , Modelos Moleculares , Estrutura Molecular
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