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1.
Eur J Med Chem ; 180: 224-237, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31306909

RESUMO

Cytotoxic effects of (R)-4'-methylklavuzon were investigated on hepatocellular carcinoma cells (HuH-7 and HepG2) and HuH-7 EpCAM+/CD133+ cancer stem cells. IC50 of (R)-4'-methylklavuzon was found as 1.25 µM for HuH-7 parental cells while it was found as 2.50 µM for HuH-7 EpCAM+/CD133+ cancer stem cells. (R)-4'-methylklavuzon tended to show more efficient in vitro cytotoxicity with its lower IC50 values on hepatocellular carcinoma cell lines compared to its lead molecule, goniothalamin and FDA-approved drugs, sorafenib and regorafenib. Cell-based Sirtuin/HDAC enzyme activity measurements revealed that endogenous Sirtuin/HDAC enzymes were reduced by 40% compared to control. SIRT1 protein levels were upregulated indicating triggered DNA repair mechanism. p53 was overexpressed in HepG2 cells. (R)-4'-methylklavuzon inhibited CRM1 protein providing increased retention of p53 and RIOK2 protein in the nucleus. HuH-7 parental and EpCAM+/CD133+ cancer stem cell spheroids lost intact morphology. 3D HepG2 spheroid viabilities were decreased in a correlation with upregulation in p53 protein levels.


Assuntos
Antígeno AC133/antagonistas & inibidores , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Molécula de Adesão da Célula Epitelial/antagonistas & inibidores , Carioferinas/antagonistas & inibidores , Neoplasias Hepáticas/tratamento farmacológico , Naftalenos/farmacologia , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Sirtuína 1/antagonistas & inibidores , Antígeno AC133/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Molécula de Adesão da Célula Epitelial/metabolismo , Células Hep G2 , Humanos , Carioferinas/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/química , Receptores Citoplasmáticos e Nucleares/metabolismo , Sirtuína 1/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
2.
Talanta ; 204: 762-768, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31357363

RESUMO

Herein we reported a two-photon (TP) fluorescence "turn-on" probe MNPO, exhibiting high selectivity and sensitivity towards intracellular cysteine (Cys) with excellent lysosomal localization. The probe displayed fast response towards Cys over homocysteine (Hcy), glutathione (GSH), and other various analytes under physiological conditions. Low cytotoxicity made it successful for TP imaging of Cys in HeLa cells with an ultralow probe concentration of 250 nM, and a rapid response of only 10 min. Simultaneously, colocalization experiments in lysosome demonstrated its ability for specific in situ detection of lysosomal Cys in living cells, which shed light on its potential applications in biomedical applications. Beyond that MNPO was successfully applied for TP imaging of Cys in mice organ tissues such as heart, liver, and spleen, and the penetration depth of mice heart tissue was up to 184 µm, which disclosed the predominant TP characteristic. We believe that this study will provide some useful information toward diagnosis and treatment of pathogenesis associated with Cys or lysosomes in future.


Assuntos
Cisteína/análise , Corantes Fluorescentes/química , Lisossomos/metabolismo , Alcenos/síntese química , Alcenos/química , Alcenos/toxicidade , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Células HeLa , Humanos , Limite de Detecção , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Naftalenos/síntese química , Naftalenos/química , Naftalenos/toxicidade , Fótons
3.
Talanta ; 203: 90-98, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31202355

RESUMO

In this work, we designed a kind of novel fluorescent probes based on naphthalene-benzoindole conjugate derived for sensitively monitoring the pH fluctuation in environment and biological systems. In the spectral method, these two probes both show significant red shift, color change and fluorescence quenching due to the effect of intramolecular charge transfer (ICT) mechanism. Moreover, we found that the probe bearing with carboxyl group displayed a more hydrophilicity than the one bearing with hydrogen atom instead, and the former exhibits a faster response and higher fluorescence intensity. Besides, the probe bearing with carboxyl group shows lower cytotoxicity, evidences by the vitro study. It indicates that this probe has great potential in application in living cell imaging as well as pH-fluctuation monitoring.


Assuntos
Corantes Fluorescentes/química , Indóis/química , Naftalenos/química , Animais , Linhagem Celular Tumoral , Colorimetria/métodos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Humanos , Concentração de Íons de Hidrogênio , Indóis/síntese química , Indóis/toxicidade , Camundongos , Microscopia de Fluorescência/métodos , Modelos Químicos , Naftalenos/síntese química , Naftalenos/toxicidade
4.
Chemistry ; 25(47): 11085-11097, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31219221

RESUMO

Naphthalene diimide (NDI) dyads exhibiting a different substitution pattern and linker length have been synthesised and evaluated as G-quadruplex (G4) ligands, by investigating their cytotoxicity in selected cell lines. The dyads with the long C7 linker exhibit extremely low IC50 values, below 10 nm, on different cancer cell lines. Contrary, the dyads with the shorter C4 linker were much less effective, with IC values increasing up to 1 µm. Among the three dyads with the longest linker, small differences in the IC50 values emerge, suggesting that the linker length plays a more important role than the substitution pattern. We have further shown that the dyads are able to induce cellular DNA damage response, which is not limited to the telomeric regions and is likely the origin of their cytotoxicity. Both absorption titration and dynamic light scattering of the most cytotoxic dyads in the presence of hTel22 highlight their ability to induce effective G4 aggregation, acting as non-covalent cross-linking agents.


Assuntos
Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Quadruplex G , Imidas/farmacologia , Naftalenos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imidas/síntese química , Imidas/química , Ligantes , Metáfase/efeitos dos fármacos , Microscopia de Fluorescência , Naftalenos/síntese química , Naftalenos/química , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Telômero/efeitos dos fármacos , Telômero/metabolismo
5.
Eur J Med Chem ; 178: 648-666, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31226656

RESUMO

Targeting autophagy is a promising therapeutic strategy for cancer treatment. As a result, the identification of novel autophagy inhibitors is an emerging field of research. Herein, we report the development of a novel AlphaScreen HTS assay that combined with a MS-based assay and a structure-based high-throughput virtual screening have enabled the identification of benzo[cd]indol-2(1H)-one as a novel scaffold that targets Atg4B. Thus, an initial screening campaign led to the identification of NSC126353 and NSC611216 bearing a chlorohydrin moiety. Structural-activity relationship analysis of the initial hits provided an optimized lead, compound 33, bearing a 7-aminobenzo[cd]indol-2-[1H]-one scaffold and a propyl group replacing the chlorine. Inhibition of autophagy was also investigated in cells by measuring LC3-II and p62 protein levels. Moreover, the synergistic effect of 33 combined with oxaliplatin resulted in an enhanced cell death in the human colorectal adenocarcinoma cell line HT-29. We are convinced that the developed AlphaScreen and MS-based assays can be key tools enabling the high-throughput identification of novel Atg4B inhibitors. Moreover, the aminobenzo[cd]indol-2-[1H]-one scaffold represents a novel chemotype for the further development of small molecule inhibitors of Atg4B.


Assuntos
Proteínas Relacionadas à Autofagia/antagonistas & inibidores , Lactamas/farmacologia , Naftalenos/farmacologia , Proteínas Relacionadas à Autofagia/metabolismo , Cisteína Endopeptidases/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Lactamas/síntese química , Lactamas/química , Modelos Moleculares , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/química , Relação Estrutura-Atividade
6.
J Agric Food Chem ; 67(22): 6414-6422, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31088051

RESUMO

The C13-norisoprenoid aroma compounds 1,1,6-trimethyl-1,2-dihydronaphthalene (TDN) and isomeric 2,10,10-trimethyl-6-methylene-1-oxaspiro[4.5]dec-7-enes, so-called vitispiranes, are considered to be biosynthetically related. They occur at higher concentrations in bottle-aged Riesling wines especially and are important contributors to the varietal aroma of Riesling wines. Because of the variation of the quantitative methods and data reported in the literature, a redetermination of concentration levels for both free and total TDN and isomeric vitispiranes, especially in German Riesling wines, was performed using a stable-isotope-dilution assay (SIDA). For this purpose, a novel six-step synthetic route to TDN and deuterium-labeled TDN was developed. A standardized sample preparation for TDN and vitispiranes and a rapid acid-hydrolysis method at genuine wine-pH conditions for the conversion of the precursors into TDN and vitispiranes were also developed. Automated HS-SPME was applied to 250 wine samples from two wine competitions, and analysis was performed by gas chromatography-mass spectrometry with selected-ion monitoring (GC-SIM-MS) as well as selected-reaction monitoring (GC-SRM-MS).


Assuntos
Deutério/química , Naftalenos/química , Norisoprenoides/química , Vinho/análise , Cromatografia Gasosa-Espectrometria de Massas , Técnicas de Diluição do Indicador , Isomerismo , Naftalenos/síntese química , Vitis/química
7.
J Antibiot (Tokyo) ; 72(7): 545-554, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30940910

RESUMO

Methicillin-resistant Staphylococcus aureus (MRSA) infections are a significant global health challenge due to the emergence of strains exhibiting resistance to nearly all classes of antibiotics. This necessitates the rapid development of novel antimicrobials to circumvent this critical problem. Screening of compounds based on phenotypes is one of the major strategies for finding new antibiotics at present. Hence, we here performed a phenotypic screening against MRSA and identified NPS-2143 exhibiting activity against MRSA with an MIC value of 16 µg ml-1. In order to discover more potent anti-MRSA agents, a series of derivatives of NPS-2143 were designed and synthesized. The most promising compounds 48 and 49 exhibited favorable antimicrobial activity with an MIC value of 2 µg ml-1.


Assuntos
Antibacterianos/síntese química , Antibacterianos/uso terapêutico , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Naftalenos/síntese química , Naftalenos/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Desenho de Drogas , Humanos , Testes de Sensibilidade Microbiana , Infecções Estafilocócicas/microbiologia , Relação Estrutura-Atividade
8.
Biomed Pharmacother ; 113: 108747, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30849638

RESUMO

Eleven dihydroxy-2-(1-hydroxy-4-methylpent-3-enyl)naphthalene derivatives as anticancer agents through regulating cell autophagy were designed and synthesized. The anticancer activity results indicated that most compounds manifested obvious un-toxic effect on GES-1 and L-02 with IC50 from 0.58 to 1.41 mM. Among them, (S,Z)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-enyl 4-(3,4- dihydroisoquinolin-2(1 H)-yl)-4-oxobut-2-enoate (compound 4i) could induce cancer cells apoptosis. Further experiments showed that autophagy played an important role in the pro-apoptotic effect of this compound. Preliminary mechanism indicated that this compound could inhibit phosphoinositide 3-kinase/protein kinase B and the mammalian target of rapamycin (PI3K/AKT/mTOR) pathway by mediating apoptosis in an autophagy-dependent manner.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Naftalenos/farmacologia , Neoplasias/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Desenho de Drogas , Humanos , Concentração Inibidora 50 , Naftalenos/síntese química , Naftalenos/química , Neoplasias/patologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/metabolismo
9.
J Antibiot (Tokyo) ; 72(6): 350-363, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30911163

RESUMO

The kedarcidin chromophore is a formidible target for total synthesis. Herein, we describe a viable synthesis of this highly unstable natural product. This entailed the early introduction and gram-scale synthesis of 2-deoxysugar conjugates of both L-mycarose and L-kedarosamine. Key advances include: (1) stereoselective allenylzinc keto-addition to form an epoxyalkyne; (2) α-selective glycosylations with 2-deoxy thioglycosides (AgPF6/DTBMP) and Schmidt donors (TiCl4); (3) Mitsunobu aryl etherification to install a hindered 1,2-cis-configuration; (4) atropselective and convergent Sonogashira-Shiina cyclization sequence; (5) Ohfune-based amidation protocol for naphthoic acid; (6) Ce(III)-mediated nine-membered enediyne cyclization and ester/mesylate derivatisation; (7) SmI2-based reductive olefination and global HF-deprotection end-game. The longest linear sequence from gram-scale intermediates is 17-steps, and HRMS data of the synthetic natural product was obtained for the first time.


Assuntos
Cicloparafinas/síntese química , Enedi-Inos/síntese química , Naftalenos/síntese química , Antineoplásicos/síntese química , Antineoplásicos/química , Cicloparafinas/química , Enedi-Inos/química , Estrutura Molecular , Naftalenos/química
10.
Org Lett ; 21(8): 2880-2884, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-30916973

RESUMO

The synthesis and utilization of a class of 2,1-borazaronaphthyltrifluoroborate reagents that provide a general solution to the challenge of N-functionalization of the 2,1-borazaronaphthalene core is described. By adorning the nitrogen of this core with a trifluoroboratomethyl unit, a suite of odd-electron processes can be executed, installing motifs that would otherwise be inaccessible using a two-electron approach. In addition, this process enables rapid annulation, furnishing a heretofore unknown polycyclic B-N species.


Assuntos
Naftalenos/síntese química , Boratos/química , Catálise , Complexos de Coordenação/química , Irídio/química , Níquel/química , Oxirredução , Processos Fotoquímicos , Rutênio/química
11.
Org Biomol Chem ; 17(15): 3765-3780, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30887974

RESUMO

Dyes with nonlinear optical (NLO) properties enable new imaging techniques and photonic systems. We have developed a dye (DANPY-1) for photonics applications in biological substrates such as nucleic acids; however, the design specification also enables it to be used for visualizing biomolecules. It is a prototype dye demonstrating a water-soluble, NLO-active fluorophore with high photostability, a large Stokes shift, and a favorable toxicity profile. A practical and scalable synthetic route to DANPY salts has been optimized featuring: (1) convergent Pd-catalyzed Suzuki coupling with pyridine 4-boronic acid, (2) site-selective pyridyl N-methylation, and (3) direct recovery of crystalline intermediates without chromatography. We characterize the optical properties, biocompatibility, and biological staining behavior of DANPY-1. In addition to stability and solubility across a range of polar media, the DANPY-1 chromophore shows a first hyperpolarizability similar to common NLO dyes such as Disperse Red 1 and DAST, a large two-photon absorption cross section for its size, substantial affinity to nucleic acids in vitro, an ability to stain a variety of cellular components, and strong sensitivity of its fluorescence properties to its dielectric environment.


Assuntos
Materiais Biocompatíveis/química , Corantes Fluorescentes/química , Naftalenos/química , Fármacos Fotossensibilizantes/química , Piridinas/química , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/farmacologia , Morte Celular/efeitos dos fármacos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Células HeLa , Humanos , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/farmacologia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/farmacologia , Piridinas/síntese química , Piridinas/farmacologia
12.
Analyst ; 144(8): 2696-2703, 2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30860221

RESUMO

A urea derivative L1 exhibits Aggregation-Induced Emission (AIE) activity in an acetonitrile-water mixed solvent. The aggregation phenomenon has been corroborated by microscopy and light scattering studies. The ligand (L1) also displays a selective turn-on fluorescence response towards human serum albumin (HSA) in 100% aqueous medium over various other comparable proteins (even bovine serum albumin (BSA)) and enzymes. The weakly emissive probe L1 showed a substantial increase in emission intensity upon binding with HSA through electrostatic interactions. The good linear relationship between the fluorescence enhancement (I/I0 - 1) and the concentration of HSA provided the scope to attain an impressive detection limit as low as 5 µg mL-1. A drug displacement experiment and molecular docking study were employed to ascertain the likely protein (HSA)-ligand binding interactions.


Assuntos
Corantes Fluorescentes/química , Albumina Sérica Humana/urina , Ureia/análogos & derivados , Antracenos/síntese química , Antracenos/química , Antracenos/metabolismo , Sítios de Ligação , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/metabolismo , Humanos , Limite de Detecção , Simulação de Acoplamento Molecular , Naftalenos/síntese química , Naftalenos/química , Naftalenos/metabolismo , Ligação Proteica , Albumina Sérica Humana/química , Albumina Sérica Humana/metabolismo , Espectrometria de Fluorescência/métodos , Ureia/síntese química , Ureia/metabolismo
13.
Molecules ; 24(3)2019 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-30717324

RESUMO

The effect of 8,8-dimethyl-3-[(R-phenyl)amino]-1,4,5(8H)-naphthalentrione derivatives (compounds 1⁻13) on the mycelial growth of Botrytis cinerea was evaluated. The fungitoxic effect depended on the substituent and its position in the aromatic ring. Compounds substituted with halogens in meta and/or para positions (compounds 3, 4, 5 and 7), methyl (compounds 8 and 9), methoxyl (compounds 10 and 11), or ethoxy-carbonyl groups (compound 12) presented higher antifungal activity than compound 1, which had an unsubstituted aromatic ring. In addition, compounds with halogens in the ortho position, such as compounds 2 and 6, and a substitution with an acetyl group in the para position (compound 13) were less active. The role of the ABC efflux pump Bctr B-type as a defense mechanism of B. cinerea against these naphthalentrione derivatives was analyzed. This pump could be involved in the detoxification of compounds 2, 6, and 13. On the contrary, this mechanism would not participate in the detoxification of compounds 1, 7, 9 and 12. Finally, the biotransformation of compound 7 by B. cinerea was studied. A mixture of two biotransformed products was obtained. One of them was compound 7A, which is reduced at C1 and C4, compared to compound 7. The other product of biotransformation, 7B, is oxidized at C7.


Assuntos
Antifúngicos/química , Botrytis/química , Micélio/efeitos dos fármacos , Naftalenos/química , Antifúngicos/síntese química , Antifúngicos/farmacologia , Biotransformação , Inativação Metabólica/efeitos dos fármacos , Micélio/crescimento & desenvolvimento , Naftalenos/síntese química , Naftalenos/farmacologia , Esporos Fúngicos/efeitos dos fármacos
14.
Future Microbiol ; 14: 235-245, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30663901

RESUMO

AIM: Novel 4-methoxy-naphthalene derivatives were synthesized based on hits structures in order to evaluate the antifungal activity against Paracoccidioides spp. METHODS: Antifungal activity of compounds was evaluated against P. brasiliensis and most promising compounds 2 and 3 were tested against eight clinically important fungal species. RESULTS: Compound 3 was the more active compound with MIC 8 to 32 µg.ml-1 for Paracoccidioides spp without toxicity monkey kidney and murine macrophagecells. Carbohydrazide 3 showed good synergistic antifungal activity with amphotericin B against P. brasiliensis specie. Titration assay of carbohydrazide 3 with PbHSD enzyme demonstrates the binding ligand-protein. Molecular dynamics simulations show that ligand 3 let the PbHSD protein more stable. CONCLUSION: New carbohydrazide 3 is an attractive lead for drug development to treat paracoccidioidomycoses.


Assuntos
Antifúngicos/farmacologia , Naftalenos/farmacologia , Paracoccidioides/efeitos dos fármacos , Paracoccidioidomicose/tratamento farmacológico , Anfotericina B/farmacologia , Animais , Antifúngicos/uso terapêutico , Combinação de Medicamentos , Sinergismo Farmacológico , Homosserina Desidrogenase/metabolismo , Hidrazinas/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Dinâmica Molecular , Naftalenos/síntese química , Naftalenos/uso terapêutico , Paracoccidioides/patogenicidade , Estabilidade Proteica , Células Vero/efeitos dos fármacos
15.
Analyst ; 144(5): 1704-1710, 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30657475

RESUMO

The superoxide anion (O2˙-) plays a crucial role in several physiological processes and many human diseases. Developing new methods for O2˙- detection in biological systems is very important. A FRET-based two-photon (TP) fluorescent probe with a ratiometric signal, TFR-O, was developed. A naphthalene derivative based TP fluorescent group was selected as the energy donor group, and a rhodol fluorescent group was chosen as the energy acceptor; the trifluoromethanesulfonate group was chosen as the recognition moiety. After reacting with O2˙-, the recognition moiety was removed and the fluorophore was released, leading to a fluorescence intensity decrease at the wavelength of 425 nm and a significant enhancement of the fluorescence intensity at 550 nm. The fluorescence intensity ratio between 550 and 425 nm (I550/I425) varied from 0.15 to 6.72, with the O2˙- concentration increasing from 0 to 50 µM. The detection limit of the TFR-O was 83 nM. Moreover, TFR-O was applied for detecting and imaging O2˙- in cells and liver tissues.


Assuntos
Fluoresceínas/química , Corantes Fluorescentes/química , Mesilatos/química , Naftalenos/química , Superóxidos/análise , Animais , Fluoresceínas/síntese química , Fluoresceínas/efeitos da radiação , Fluoresceínas/toxicidade , Fluorescência , Transferência Ressonante de Energia de Fluorescência/métodos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/efeitos da radiação , Corantes Fluorescentes/toxicidade , Limite de Detecção , Fígado/metabolismo , Mesilatos/síntese química , Mesilatos/efeitos da radiação , Mesilatos/toxicidade , Camundongos , Naftalenos/síntese química , Naftalenos/efeitos da radiação , Naftalenos/toxicidade , Fótons , Células RAW 264.7 , Superóxidos/metabolismo
16.
Eur J Med Chem ; 163: 160-168, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30503940

RESUMO

A series of 19 analogues of the antiproliferative naphthopyran LY290181 were prepared for structure-activity relationship studies. We found the best activities for test compounds bearing small substituents at the meta position of the phenyl ring. The mode of action of LY290181 and eight new analogues was studied in detail. The compounds were highly anti-proliferative with IC50 values in the sub-nanomolar to triple-digit nanomolar range. The new analogues led to G2/M arrest due to interruption of the microtubule dynamics. In 518A2 melanoma cells they caused a mitotic catastrophe which eventually led to apoptosis. The naphthopyrans also induced a disruption of the vasculature in the chorioallantoic membrane (CAM) of fertilized chicken eggs as well as in xenograft tumors in mice. In a preliminary therapy trial, the difluoro derivative 2b retarded the growth of resistant xenograft tumors in mice.


Assuntos
Antineoplásicos/síntese química , Vasos Sanguíneos/efeitos dos fármacos , Naftalenos/síntese química , Piranos/síntese química , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Embrião de Galinha , Membrana Corioalantoide/irrigação sanguínea , Xenoenxertos , Humanos , Camundongos , Naftalenos/farmacologia , Piranos/farmacologia , Relação Estrutura-Atividade
17.
Bioorg Med Chem Lett ; 29(1): 78-82, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30442421

RESUMO

Methyltrioxorhenium mediated oxidative addition/elimination nucleophilic substitution yielded alkylamino and arylamino cambinol derivatives characterized by anti-proliferative activity against wild-type and p53 mutated MGH-U1 and RT112 bladder cancer cell lines. Some of the novel compounds showed an activity higher than that of the lead compound. The reaction was highly regioselective, affording for the first time a panel of C-2 cambinol substitution products. Aliphatic primary and secondary amines, and primary aromatic amines, were used as nitrogen centered nucleophiles. Surprisingly, the antiproliferative activity of C-2 substituted cambinol derivatives was not correlated to the induction of p53 protein, as evaluated by the analysis of the cell viability on wild-type and p53 mutated cancer cell lines, and further confirmed by western blot analyses. These data suggest that they exert their antiproliferative activity by a mechanism completely different from cambinol.


Assuntos
Antineoplásicos/farmacologia , Naftalenos/farmacologia , Pirimidinonas/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/química , Oxirredução , Pirimidinonas/síntese química , Pirimidinonas/química , Relação Estrutura-Atividade , Neoplasias da Bexiga Urinária/patologia
18.
Spectrochim Acta A Mol Biomol Spectrosc ; 210: 266-274, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30466032

RESUMO

A simple naphthalene derivative, 6-hydroxy-2-naphthohydrazide (NAH), was designed and synthesized through two facile steps reactions with the 6-hydroxy-2-naphthoic acid (NCA) as the starting material. In neat H2O (10% 0.01 M HEPES buffer, v/v, pH = 7.4), probe NAH showed a highly selective and sensitive response towards Fe3+ via perceptible color change and displayed "turn-on" dual-emission fluorescence response for Cu2+. The binding stoichiometry ratio of NAH/Cu2+ and NAH/Fe3+ were all confirmed as 1:1 by the method of fluorescence job's plot and UV-Vis job's plot, respectively. Probe NAH can be used over a wide pH range for the determination of Fe3+ (2.0-10.0) and Cu2+ (6.0-10.0) without interference from other co-existing metal ions. A possible detection mechanism was the hydrolysis of NAH upon the addition of Fe3+ or Cu2+, thereby leading to the formation of 6-hydroxy-naphthalene-2-carboxylic acid (NCA) which was further confirmed by the various spectroscopic techniques including FT-IR, 1H NMR titration and HRMS. Moreover, NAH was successfully applied to the detection of Cu2+ and Fe3+ in tap water, ultrapure water and BSA.


Assuntos
Colorimetria/métodos , Cobre/análise , Corantes Fluorescentes/química , Hidrazinas/química , Ferro/análise , Naftalenos/química , Água/análise , Cobre/química , Corantes Fluorescentes/síntese química , Hidrazinas/síntese química , Concentração de Íons de Hidrogênio , Hidrólise , Ferro/química , Espectroscopia de Ressonância Magnética , Metais/química , Naftalenos/síntese química , Sensibilidade e Especificidade , Soroalbumina Bovina/análise , Soroalbumina Bovina/química , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier
19.
Bioorg Med Chem ; 27(2): 343-353, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30552006

RESUMO

Inhibitors for NorA efflux pump of Staphylococcus aureus have attracted the attention of many researchers towards the discovery and development of novel efflux pump inhibitors (EPIs). In an attempt to find specific potent inhibitors of NorA efflux pump of S. aureus, a total of 15 amino acid conjugates of 3-(1-chloro-3,4-dihydronaphthalen-2-yl)acrylic acid (4-18) were synthesized using a simple convenient synthetic approach and bioevaluated against NorA efflux pump. Two compounds 7 and 8 (each having MEC of 1.56 µg/mL) were found to restore the activity of ciprofloxacin through reduction of the MIC elucidated by comparing the ethidium bromide efflux in dose dependent manner in addition to ethidium bromide efflux inhibition and accumulation study using NorA overexpressing strain SA-1199B. Most potent compounds among these were able to restore the antibacterial activity of ciprofloxacin completely against SA-1199B. Structure activity relationship (SAR) studies and docking study of potent compounds 7 and 8 could elucidate the structural requirements necessary for interaction with the NorA efflux pumps. On the whole, compounds 7 and 8 have ability to reverse the NorA efflux mediated resistance and could be further optimized for development of potent efflux pump inhibitors.


Assuntos
Acrilamidas/farmacologia , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Naftalenos/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Acrilamidas/síntese química , Acrilamidas/química , Antibacterianos/síntese química , Antibacterianos/química , Proteínas de Bactérias/química , Sítios de Ligação , Ciprofloxacino/farmacologia , Sinergismo Farmacológico , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos/química , Naftalenos/síntese química , Naftalenos/química , Relação Estrutura-Atividade
20.
Yakugaku Zasshi ; 138(11): 1353-1361, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-30381643

RESUMO

Heterogeneous metal catalysts constitute a very important tool for the synthesis of functional materials and fine chemicals owing to their high efficiency, robustness, and facile recyclability. Biaryls are privileged structural motifs in many natural products, chiral ligands, and catalysts. The oxidative biaryl coupling reaction is one of the most promising methods for biaryl synthesis in terms of atom and step economies. However, although oxidative biaryl coupling of naphthols has been studied thoroughly, the coupling of aryl amines providing biaryl amines like 2,2'-diamino-1,1'-binaphthyl (BINAM) and 2-amino-2'-hydroxy-1,1'-binaphthyl (NOBIN) derivatives remains elusive. Recently, we have found that aryl amines are efficiently dimerized with the use of a heterogeneous Rh/C catalyst under acidic conditions. This heterogeneously catalyzed method can be adapted to the highly selective cross-coupling reaction of aryl amines and the intramolecular biaryl coupling reaction. Furthermore, we developed an aerobic direct C-H oxidation of polycyclic aromatics catalyzed by a recyclable heterogeneous rhodium catalyst. These methodologies are advantageous compared with the existing reactions owing to the mild aerobic conditions employed and the facile recyclability of the heterogeneous catalysts used.


Assuntos
Antracenos/química , Química Orgânica/métodos , Naftalenos/química , Naftalenos/síntese química , Naftóis/química , Naftóis/síntese química , Aminas/química , Catálise , Estrutura Molecular , Fenômenos de Química Orgânica , Oxirredução , Ródio/química
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