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1.
Pharmacol Rev ; 71(4): 450-466, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31471460

RESUMO

Despite continuous clinical use for more than 170 years, the mechanism of general anesthetics has not been completely characterized. In this review, we focus on the role of voltage-gated sodium channels in the sedative-hypnotic actions of halogenated ethers, describing the history of anesthetic mechanisms research, the basic neurobiology and pharmacology of voltage-gated sodium channels, and the evidence for a mechanistic interaction between halogenated ethers and sodium channels in the induction of unconsciousness. We conclude with a more integrative perspective of how voltage-gated sodium channels might provide a critical link between molecular actions of the halogenated ethers and the more distributed network-level effects associated with the anesthetized state across species.


Assuntos
Éteres/farmacologia , Inconsciência/induzido quimicamente , Inconsciência/metabolismo , Canais de Sódio Disparados por Voltagem/metabolismo , Animais , Éteres/química , Humanos , Hidrocarbonetos Halogenados/química , Hidrocarbonetos Halogenados/farmacologia , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/farmacologia
2.
J Agric Food Chem ; 67(43): 11893-11900, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31542926

RESUMO

To explore a novel fungicide effectively against cucumber downy mildew (CDM), a series of new arylpyrazole containing pyrimidine ether derivatives were designed and synthesized by employing the intermediate derivatization method (IDM). The structures of synthesized compounds were identified by 1H NMR, 13C NMR, elemental analyses, MS, and X-ray diffraction. Bioassays demonstrated that some of the title compounds exhibited excellent fungicidal activities against CDM. Especially, compound 7 (EC50 = 1.22 mg/L) displayed significantly higher bioactivity than that of commercial fungicides diflumetorim and flumorph and nearly equal effect to that of cyazofamid. The relationship between the structure and fungicidal activity of the synthesized compounds was discussed as well. The study showed that compound 7 was a promising fungicide candidate for further development.


Assuntos
Éteres/química , Fungicidas Industriais/síntese química , Fungicidas Industriais/farmacologia , Pirimidinas/química , Cucumis sativus/microbiologia , Desenho de Fármacos , Éteres/farmacologia , Fungicidas Industriais/química , Estrutura Molecular , Oomicetos/efeitos dos fármacos , Doenças das Plantas/microbiologia , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Difração de Raios X
3.
J Enzyme Inhib Med Chem ; 34(1): 999-1009, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31072143

RESUMO

This study explored the possible bioactive ingredients and target protein of Rostellularia procumbens (L.) Nees. The results of optical turbidimetry revealed that the ethyl acetate extraction obtained from R. procumbens (L.) Nees could inhibit platelet aggregation. Gene chip was used to investigate differentially expressed genes. According to the results of the gene chip, the targets of compounds isolated from the ethyl acetate extraction were predicted by network pharmacology. Computational studies revealed that chinensinaphthol methyl ether and neojusticin B may target the integrin αIIbß3 protein. The results of Prometheus NT.48 and microscale thermophoresis suggested that the molecular interactions between the two compounds with purified integrin αIIbß3 protein in the optimal test conditions were coherent with the docking results. To our best knowledge, this is the first report to state that chinensinaphthol methyl ether and neojusticin B target the integrin αIIbß3 protein.


Assuntos
Acanthaceae/química , Derivados de Benzeno/farmacologia , Dioxolanos/farmacologia , Éteres/farmacologia , Lignanas/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Derivados de Benzeno/química , Derivados de Benzeno/isolamento & purificação , Dioxolanos/química , Dioxolanos/isolamento & purificação , Relação Dose-Resposta a Droga , Éteres/química , Éteres/isolamento & purificação , Humanos , Lignanas/química , Lignanas/isolamento & purificação , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/isolamento & purificação , Testes de Função Plaquetária , Relação Estrutura-Atividade
4.
Mar Drugs ; 17(3)2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30897777

RESUMO

Chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD), cystic fibrosis, and asthma, are some of the leading causes of illness and fatalities worldwide. The search for novel treatments led to the exploration of marine natural products as drug candidates to combat the debilitating effects of mucus accumulation and chronic inflammation. Previous research showed that an alga-derived compound, brevenal, could attenuate the effects of inflammatory agents, but the mechanisms by which it exerted its effects remained unclear. We investigated the effects of brevenal on lipopolysaccharide (LPS) induced cytokine/chemokine production from murine macrophages and human lung epithelial cells. It was found that brevenal reduces proinflammatory mediator secretion while preserving anti-inflammatory secretion from these cells. Furthermore, we found that brevenal does not alter cell surface Toll-like receptor 4 (TLR4) expression, thereby maintaining the cells' ability to respond to bacterial infection. However, brevenal does alter macrophage activation states, as demonstrated by reduced expression of both M1 and M2 phenotype markers, indicating this putative anti-inflammatory drug shifts innate immune cells to a less active state. Such a mechanism of action would be ideal for reducing inflammation in the lung, especially with patients suffering from chronic respiratory diseases, where inflammation can be lethal.


Assuntos
Anti-Inflamatórios/farmacologia , Organismos Aquáticos/química , Dinoflagelados/química , Éteres/farmacologia , Fatores Imunológicos/farmacologia , Polímeros/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Linhagem Celular Tumoral , Doença Crônica/terapia , Avaliação Pré-Clínica de Medicamentos , Células Epiteliais/efeitos dos fármacos , Éteres/uso terapêutico , Humanos , Fatores Imunológicos/uso terapêutico , Pulmão/citologia , Macrófagos/efeitos dos fármacos , Camundongos , Polímeros/uso terapêutico , Mucosa Respiratória/citologia , Doenças Respiratórias/tratamento farmacológico , Doenças Respiratórias/imunologia
5.
Neuropharmacology ; 150: 100-111, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30836092

RESUMO

Inhibition of postsynaptic density protein-95 (PSD-95) decouples N-methyl-d-aspartate (NMDA) receptor downstream signaling and results in neuroprotection after focal cerebral ischemia. We have previously developed UCCB01-144, a dimeric PSD-95 inhibitor, which binds PSD-95 with high affinity and is neuroprotective in experimental stroke. Here, we investigate the selectivity, efficacy and toxicity of UCCB01-144 and compare with the monomeric drug candidate Tat-NR2B9c. Fluorescence polarization using purified proteins and pull-downs of mouse brain lysates showed that UCCB01-144 potently binds all four PSD-95-like membrane-associated guanylate kinases (MAGUKs). In addition, UCCB01-144 affected NMDA receptor signaling pathways in ischemic brain tissue. UCCB01-144 reduced infarct size in young and aged male mice at various doses when administered 30 min after permanent middle cerebral artery occlusion, but UCCB01-144 was not effective in young male mice when administered 1 h post-ischemia or in female mice. Furthermore, UCCB01-144 was neuroprotective in a transient stroke model in rats, and in contrast to Tat-NR2B9c, high dose of UCCB01-144 did not lead to significant changes in mean arterial blood pressure or heart rate. Overall, UCCB01-144 is a potent MAGUK inhibitor that reduces neurotoxic PSD-95-mediated signaling and improves neuronal survival following focal brain ischemia in rodents under various conditions and without causing cardiovascular side effects, which encourages further studies towards clinical stroke trials.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Proteína 4 Homóloga a Disks-Large/antagonistas & inibidores , Éteres/farmacologia , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Encéfalo/patologia , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Éteres/efeitos adversos , Éteres/uso terapêutico , Feminino , Masculino , Camundongos , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/uso terapêutico , Ratos , Fatores de Tempo
6.
Mar Drugs ; 17(3)2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30875760

RESUMO

The marine alga, Symphyocladia latiuscula (Harvey) Yamada, is a good source of bromophenols with numerous biological activities. This study aims to characterize the anti-diabetic potential of 2,3,6-tribromo-4,5-dihydroxybenzyl derivatives isolated from S. latiuscula via their inhibition of tyrosine phosphatase 1B (PTP1B) and α-glucosidase. Additionally, this study uses in silico modeling and glucose uptake potential analysis in insulin-resistant (IR) HepG2 cells to reveal the mechanism of anti-diabetic activity. This bioassay-guided isolation led to the discovery of three potent bromophenols that act against PTP1B and α-glucosidase: 2,3,6-tribromo-4,5-dihydroxybenzyl alcohol (1), 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether (2), and bis-(2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether) (3). All compounds inhibited the target enzymes by 50% at concentrations below 10 µM. The activity of 1 and 2 was comparable to ursolic acid (IC50; 8.66 ± 0.82 µM); however, 3 was more potent (IC50; 5.29 ± 0.08 µM) against PTP1B. Interestingly, the activity of 1⁻3 against α-glucosidase was 30⁻110 times higher than acarbose (IC50; 212.66 ± 0.35 µM). Again, 3 was the most potent α-glucosidase inhibitor (IC50; 1.92 ± 0.02 µM). Similarly, 1⁻3 showed concentration-dependent glucose uptake in insulin-resistant HepG2 cells and downregulated PTP1B expression. Enzyme kinetics revealed different modes of inhibition. In silico molecular docking simulations demonstrated the importance of the 7⁻OH group for H-bond formation and bromine/phenyl ring number for halogen-bond interactions. These results suggest that bromophenols from S. latiuscula, especially highly brominated 3, are inhibitors of PTP1B and α-glucosidase, enhance insulin sensitivity and glucose uptake, and may represent a novel class of anti-diabetic drugs.


Assuntos
Compostos de Benzil/farmacologia , Diabetes Mellitus/tratamento farmacológico , Éteres/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Rodófitas/química , alfa-Glucosidases/metabolismo , Compostos de Benzil/química , Compostos de Benzil/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Éteres/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/farmacologia , Células Hep G2 , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Resistência à Insulina , Simulação de Acoplamento Molecular
7.
Toxins (Basel) ; 11(2)2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30717108

RESUMO

Gambierdiscus species are the producers of the marine toxins ciguatoxins and maitotoxins which cause worldwide human intoxications recognized as Ciguatera Fish Poisoning. A deep chemical investigation of a cultured strain of G. belizeanus, collected in the Caribbean Sea, led to the identification of a structural homologue of the recently described gambierone isolated from the same strain. The structure was elucidated mainly by comparison of NMR and MS data with those of gambierone and ascertained by 2D NMR data analyses. Gratifyingly, a close inspection of the MS data of the new 44-methylgambierone suggests that this toxin would actually correspond to the structure of maitotoxin-3 (MTX3, m/z 1039.4957 for the protonated adduct) detected in 1994 in a Pacific strain of Gambierdiscus and recently shown in routine monitoring programs. Therefore, this work provides for the first time the chemical identification of the MTX3 molecule by NMR. Furthermore, biological data confirmed the similar activities of both gambierone and 44-methylgambierone. Both gambierone and MTX3 induced a small increase in the cytosolic calcium concentration but only MTX3 caused cell cytotoxicity at micromolar concentrations. Moreover, chronic exposure of human cortical neurons to either gambierone or MTX3 altered the expression of ionotropic glutamate receptors, an effect already described before for the synthetic ciguatoxin CTX3C. However, even when gambierone and MTX3 affected glutamate receptor expression in a similar manner their effect on receptor expression differed from that of CTX3C, since both toxins decreased AMPA receptor levels while increasing N-methyl-d-aspartate (NMDA) receptor protein. Thus, further studies should be pursued to clarify the similarities and differences in the biological activity between the known ciguatoxins and the new identified molecule as well as its contribution to the neurological symptoms of ciguatera.


Assuntos
Toxinas Marinhas/química , Toxinas Marinhas/farmacologia , Oxocinas/química , Oxocinas/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ciguatoxinas/farmacologia , Dinoflagelados , Éteres/química , Éteres/farmacologia , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Receptores de Glutamato/metabolismo
8.
J Biol Inorg Chem ; 24(2): 191-210, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30673878

RESUMO

Zinc(II) (5), indium(III) (6), and lutetium(III) (7) phthalocyanines (Pcs) peripherally substituted with poly (ethylene glycol) (PEG) monomethyl ether 2000 (PEGME-2000) blocks were synthesized via Sonogashira coupling reaction with high yields and their photophysical, photochemical and photobiological properties were investigated. We elucidated the interactions of these compounds with calf thymus DNA and bovine serum albumin (BSA), and determined K(DNA) and K(BSA) binding constants at degrees of 105 and 106, respectively. Singlet oxygen quantum yields were found (Ф∆ = 0.44, 0.54, and 0.68 for 5, 6, and 7, respectively). Thermodynamic parameters, as well as thermal denaturation profile of double-stranded CT-DNA were examined to determine the type of binding mode. According to our experimental data, we report that PEGME-2000 favors the formation of binary complex between DNA, and phthalocyanine complexes. Therein, thermodynamic data suggest that this binding mode is indeed spontaneous under reported conditions, and rather non-specific. Additionally, Pcs 5, 6, and 7 substituted with PEGME-2000 blocks showed antimicrobial activity against Gram-positive and Gram-negative bacteria, as well as fungi (yeast), and Pc 5 had the highest antimicrobial activity among them, as revealed by disc diffusion assay results. In short, our results suggest that these compounds could be used for photodynamic therapy, they have both antibacterial and antifungal activity, and the binding ability of new phthalocyanines 5, 6, and 7 with BSA paves the way for their utilization as drug vehicle in blood plasma.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Bovinos , DNA/química , Éteres/química , Éteres/farmacologia , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Índio/química , Índio/farmacologia , Indóis/química , Indóis/farmacologia , Lutécio/química , Lutécio/farmacologia , Testes de Sensibilidade Microbiana , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Processos Fotoquímicos , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Soroalbumina Bovina/química
9.
Eur J Med Chem ; 166: 32-47, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30684869

RESUMO

Despite some progress in recent years, the fight against parasitic diseases still remains a great challenge. Parasitic diseases affect primarily (but not exclusively) the poorest people living in underdeveloped regions of the world. The distribution of parasitoses are linked to tropical and subtropical climate conditions, to population growth and to impoverishment. If not treated, parasitic diseases may lead to serious health problems, and even death. Particularly vulnerable groups include infants and young children, pregnant women and immunocompromised individuals. Polyether ionophore antibiotics (ionophores), traditionally used in veterinary medicine as anti-coccidial feed additives and non-hormonal growth promoters, are of considerable interest, as they have been found to be highly effective agents against various parasites, both in vitro and in vivo. This review summarizes the anti-parasitic effects of the most important polyether ionophores against parasites that are responsible for a number of animal and human parasitic diseases. Recent findings and advances that support the potential of polyether ionophore antibiotics as novel anti-parasitic drug candidates are also presented and discussed.


Assuntos
Antiparasitários/química , Antiparasitários/farmacologia , Éteres/química , Éteres/farmacologia , Ionóforos/química , Ionóforos/farmacologia , Parasitos/efeitos dos fármacos , Animais , Humanos
10.
Dalton Trans ; 48(4): 1292-1313, 2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30608086

RESUMO

Rational ligand design approaches allowed {Cu2(µ-OH/OMe)} cores to be accommodated within µ-phenoxido bis(tetradentate) and µ-phenoxido bis(tridentate) ligands having thioether donors. The complexes [Cu2(µ-H2L1)(µ-OH)](ClO4)2·2H2O (1), [Cu2(µ-L2)(µ-OH)(OH2)](ClO4)2 (2a) and [Cu2(µ-L2)(µ-OCH3)(OH2)](ClO4)2 (2b) were obtained from an N2O3S2 donor set bearing the H3L1 ligand (2,6-bis-[{2-(2-hydroxyethylthio)ethylimino}methyl]-4-methylphenol) and N2OS2 donor set containing the HL2 ligand (4-methyl-2,6-bis-[{2-(methylthio)phenylimino}methyl]phenol) without showing double phenoxido bridging or any type of preformed inter-fragment aggregation. Previously, we showed that H3L (2,6-bis[((2-(2-hydroxyethoxy)ethyl)imino)methyl]-4-methylphenol), the ether analogue of H3L1, in the presence of carboxylate anions, was responsible for the self-aggregation of preformed {Cu2} fragments and gave two types of [Cu4] complexes comprising [Cu4O] and [Cu4(OH)2] cores (T. S. Mahapatra, A. Bauzá, D. Dutta, S. Mishra, A. Frontera and D. Ray, ChemistrySelect, 2016, 1, 64-74). The molecular structures of 1, 2a and 2b were determined via single crystal X-ray diffraction and solution studies, which indicated the presence of [Cu2] species. This was further confirmed via UV-vis spectroscopy and HRMS analysis. The synthesized complexes were screened for their potential as catalysts for the catalytic oxidation of 3,5-di-tert-butylcatechol (3,5-DTBCH2). A change in the mechanism of catalytic oxidation was observed with a change in the ligand backbone. All three complexes also showed DNA binding properties, which were further substantiated via molecular docking studies. Their DNA binding affinities were quantitatively ascertained using their intrinsic binding constant, Kb, values which were found to be 4.2 × 104, 5.6 × 104 and 4.8 × 104 M-1, respectively. Furthermore, the complexes displayed efficient DNA cleavage behaviour with pBR322 and the oxidative path was established in presence of ROS, singlet oxygen, 1O2, and the superoxide anion, O2·-.


Assuntos
Catecol Oxidase/metabolismo , Complexos de Coordenação/farmacologia , Clivagem do DNA/efeitos dos fármacos , DNA/metabolismo , Catecóis/metabolismo , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cobre/química , Cobre/farmacologia , DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Éteres/química , Éteres/farmacologia , Peróxido de Hidrogênio/análise , Concentração de Íons de Hidrogênio , Cinética , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxirredução , Relação Estrutura-Atividade , Compostos de Sulfidrila/química , Compostos de Sulfidrila/farmacologia , Enxofre/química , Enxofre/farmacologia
11.
Eur J Med Chem ; 161: 543-558, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30391816

RESUMO

A series of novel phenol ether derivatives were designed, synthesized, and evaluated as non-covalent proteasome inhibitors. Most compounds exhibited moderate to excellent proteasome inhibitory activity. In particular, compound 18x proved to be the most potent compound (chymotrypsin-like: IC50 = 49 nM), exhibiting a 2-fold higher potency compared to the reported PI-1840. Besides, compound 18x exhibited excellent metabolic stability and selective anti-proliferative activity against solid cancer cell lines including HepG2 and HGC27, providing incentive for the further development as a potential anticancer agent against solid cancers.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Éteres/farmacologia , Fenóis/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Éteres/síntese química , Éteres/química , Humanos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Fenóis/síntese química , Fenóis/química , Inibidores de Proteassoma/síntese química , Inibidores de Proteassoma/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
12.
BMC Pharmacol Toxicol ; 19(1): 57, 2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30217234

RESUMO

BACKGROUND: NMDA receptor modulation by hydrocarbons is associated with a molar water solubility cut-off. Low-affinity phenolic modulation of GABAA receptors is also associated with a cut-off, but at much lower molar solubility values. We hypothesized that other anesthetic-sensitive ion channels exhibit distinct cut-off effects associated with hydrocarbon molar water solubility, and that cut-off values are comparatively similar between related receptors than phylogenetically distant ones. METHODS: Glycine or GABAA receptors or TREK-1, TRESK, Nav1.2, or Nav1.4 channels were expressed separately in frog oocytes. Two electrode voltage clamp techniques were used to study current responses in the presence and absence of hydrocarbon series from eight functional groups with progressively increasing size at saturated aqueous concentrations. Null response (cut-off) was defined by current measurements that were statistically indistinguishable between baseline and hydrocarbon exposure. RESULTS: Ion channels exhibited cut-off effects associated with hydrocarbon molar water solubility in the following order of decreasing solubility: Nav1.2 ≈ Nav1.4 ≳ TRESK ≈ TREK-1 > GABAA >> glycine. Previously measured solubility cut-off values for NMDA receptors were intermediate between those for Nav1.4 and TRESK. CONCLUSIONS: Water solubility cut-off responses were present for all anesthetic-sensitive ion channels; distinct cut-off effects may exist for all cell surface receptors that are sensitive to volatile anesthetics. Suggested is the presence of amphipathic receptor sites normally occupied by water molecules that have dissociation constants inversely related to the cut-off solubility value. Poorly soluble hydrocarbons unable to reach concentrations sufficient to out-compete water for binding site access fail to modulate the receptor.


Assuntos
Anestésicos/química , Anestésicos/farmacologia , Canais Iônicos/fisiologia , Álcoois/química , Álcoois/farmacologia , Aminas/química , Aminas/farmacologia , Animais , Éteres/química , Éteres/farmacologia , Feminino , Hidrocarbonetos/química , Hidrocarbonetos/farmacologia , Oócitos/fisiologia , Solubilidade , Água/química , Xenopus laevis
13.
Bioorg Med Chem Lett ; 28(11): 2050-2054, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29748053

RESUMO

A series of diaryl ethers were designed and synthesized to discern the structure activity relationships against the two closely related mono-(ADP-ribosyl)transferases PARP10 and PARP14. Structure activity studies identified 8b as a sub-micromolar inhibitor of PARP10 with ∼15-fold selectivity over PARP14. In addition, 8k and 8m were discovered to have sub-micromolar potency against PARP14 and demonstrated moderate selectivity over PARP10. A crystal structure of the complex of PARP14 and 8b shows binding of the compound in a novel hydrophobic pocket and explains both potency and selectivity over other PARP family members. In addition, 8b, 8k and 8m also demonstrate selectivity over PARP1. Together, this study identified novel, potent and metabolically stable derivatives to use as chemical probes for these biologically interesting therapeutic targets.


Assuntos
Amidas/farmacologia , Desenho de Fármacos , Éteres/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Relação Dose-Resposta a Droga , Éteres/síntese química , Éteres/química , Humanos , Estrutura Molecular , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases/química , Proteínas Proto-Oncogênicas/metabolismo , Relação Estrutura-Atividade
14.
ChemMedChem ; 13(13): 1353-1362, 2018 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-29756273

RESUMO

Despite major strides in reducing Plasmodium falciparum infections, this parasite still accounts for roughly half a million annual deaths. This problem is compounded by the decreased efficacy of artemisinin combination therapies. Therefore, the development and optimisation of novel antimalarial chemotypes is critical. In this study, we describe our strategic approach to optimise a class of previously reported antimalarials, resulting in the discovery of 1-(5-chloro-1H-indol-3-yl)-2-[(4-cyanophenyl)thio]ethanone (13) and 1-(5-chloro-1H-indol-3-yl)-2-[(4-nitrophenyl)thio]ethanone (14), whose activity was equipotent to that of chloroquine against the P. falciparum 3D7 strain. Furthermore, these compounds were found to be nontoxic to HeLa cells as well as being non-haemolytic to uninfected red blood cells. Intriguingly, several of our most promising compounds were found to be less active against the isogenic NF54 strain, highlighting possible issues with long-term dependability of malarial strains. Finally compound 14 displayed similar activity against both the NF54 and K1 strains, suggesting that it inhibits a pathway that is uncompromised by K1 resistance.


Assuntos
Antimaláricos/farmacologia , Éteres/farmacologia , Indóis/farmacologia , Sulfetos/farmacologia , Antimaláricos/síntese química , Antimaláricos/química , Antimaláricos/toxicidade , Eritrócitos/efeitos dos fármacos , Éteres/síntese química , Éteres/química , Éteres/toxicidade , Células HeLa , Hemólise/efeitos dos fármacos , Humanos , Indóis/síntese química , Indóis/química , Indóis/toxicidade , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfetos/síntese química , Sulfetos/química , Sulfetos/toxicidade
15.
ChemMedChem ; 13(12): 1193-1209, 2018 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-29771004

RESUMO

Cancer continues to be a worldwide health problem. Certain macrocyclic molecules have become attractive therapeutic alternatives for this disease because of their efficacy and, frequently, their novel mechanisms of action. Herein, we report the synthesis of a series of 20-, 21-, and 22-membered macrocycles containing triazole and bis(aryl ether) moieties. The compounds were prepared by a multicomponent approach from readily available commercial substrates. Notably, some of the compounds displayed interesting cytotoxicity against cancer (PC-3) and breast (MCF-7) cell lines, especially those bearing an aliphatic or a trifluoromethyl substituent on the N-phenyl moiety (IC50 <13 µm). Additionally, some of the compounds were able to induce apoptosis relative to the solvent control; in particular, (Z)-N-cyclohexyl-7-oxo-6-[4-(trifluoromethyl)phenyl]-11 H-3,10-dioxa-6-aza-1(4,1)-triazola-4(1,3),9(1,4)-dibenzenacyclotridecaphane-5-carboxamide (12 f) was the most potent in this regard (22.7 % of apoptosis).


Assuntos
Antineoplásicos/farmacologia , Éteres/farmacologia , Compostos Macrocíclicos/farmacologia , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Éteres/síntese química , Éteres/química , Humanos , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
16.
Proc Natl Acad Sci U S A ; 115(16): 4246-4251, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29610346

RESUMO

Flaviviruses enter host cells through the process of clathrin-mediated endocytosis, and the spectrum of host factors required for this process are incompletely understood. Here we found that lymphocyte antigen 6 locus E (LY6E) promotes the internalization of multiple flaviviruses, including West Nile virus, Zika virus, and dengue virus. Perhaps surprisingly, LY6E is dispensable for the internalization of the endogenous cargo transferrin, which is also dependent on clathrin-mediated endocytosis for uptake. Since viruses are substantially larger than transferrin, we reasoned that LY6E may be required for uptake of larger cargoes and tested this using transferrin-coated beads of similar size as flaviviruses. LY6E was indeed required for the internalization of transferrin-coated beads, suggesting that LY6E is selectively required for large cargo. Cell biological studies found that LY6E forms tubules upon viral infection and bead internalization, and we found that tubule formation was dependent on RNASEK, which is also required for flavivirus internalization, but not transferrin uptake. Indeed, we found that RNASEK is also required for the internalization of transferrin-coated beads, suggesting it functions upstream of LY6E. These LY6E tubules resembled microtubules, and we found that microtubule assembly was required for their formation and flavivirus uptake. Since microtubule end-binding proteins link microtubules to downstream activities, we screened the three end-binding proteins and found that EB3 promotes virus uptake and LY6E tubularization. Taken together, these results highlight a specialized pathway required for the uptake of large clathrin-dependent endocytosis cargoes, including flaviviruses.


Assuntos
Flavivirus/fisiologia , Internalização do Vírus , Antígenos de Superfície/genética , Antígenos de Superfície/fisiologia , Linhagem Celular Tumoral , Vírus da Dengue/fisiologia , Endocitose/efeitos dos fármacos , Endocitose/fisiologia , Endorribonucleases/fisiologia , Éteres/farmacologia , Proteínas Ligadas por GPI/deficiência , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/fisiologia , Técnicas de Silenciamento de Genes , Humanos , Microesferas , Proteínas Associadas aos Microtúbulos/fisiologia , Microtúbulos/efeitos dos fármacos , Microtúbulos/fisiologia , Nocodazol/farmacologia , Compostos de Espiro/farmacologia , Transferrina , Vírus do Nilo Ocidental/fisiologia , Zika virus/fisiologia
17.
Molecules ; 23(3)2018 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-29534537

RESUMO

A series of oxime ethers with C6-C4 fragment was designed and virtually bioactively screened by docking with a target, then provided by a Friedel-Crafts reaction, esterification (or amidation), and oximation from p-substituted phenyl derivatives (Methylbenzene, Methoxybenzene, Chlorobenzene). Anti-hepatitis B virus (HBV) activities of all synthesized compounds were evaluated with HepG2.2.15 cells in vitro. Results showed that most of compounds exhibited low cytotoxicity on HepG2.2.15 cells and significant inhibition on the secretion of HBsAg and HBeAg. Among them, compound 5c-1 showed the most potent activity on inhibiting HBsAg secretion (IC50 = 39.93 µM, SI = 28.51). Results of the bioactive screening showed that stronger the compounds bound to target human leukocyte antigen A protein in docking, the more active they were in anti-HBV activities in vitro.


Assuntos
Antivirais/farmacologia , Éteres/farmacologia , Vírus da Hepatite B/metabolismo , Oximas/farmacologia , Antivirais/química , Avaliação Pré-Clínica de Medicamentos , Éteres/química , Antígenos HLA-A/química , Antígenos HLA-A/metabolismo , Células Hep G2 , Antígenos de Superfície da Hepatite B/metabolismo , Antígenos E da Hepatite B/metabolismo , Vírus da Hepatite B/crescimento & desenvolvimento , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Oximas/química
18.
Eur J Med Chem ; 150: 864-875, 2018 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-29597169

RESUMO

As a contribution to the development of novel coumarin-oxime ether conjugates with therapeutically interesting properties, a series of coumarin-oxime ether (1a-1j) was synthesised using SN2 reaction of bromomethyl coumarins with butane-2,3-dione monoxime. Invitro anti-tuberculosis activityagainstMTBH37Rv strain was established for the coumarin-oxime ether (1a-1j). Most of the compounds exhibited significant activity with minimum inhibitory concentration (MIC)in the range of 0.04-3.12 µg mL-1. Compound (1h) was identified as a hit candidate exhibiting MIC of 0.04 µg mL-1, closer to the MIC value of Isoniazid (0.02 µg mL-1), a commercially available drug for the treatment of tuberculosis. Compound 1h also displayed a low level of toxicity in Vero cells along with a good safety profile in vitro. Compounds that showed potent anti-tubercular activity were also found to cleave DNA more efficiently and thereby exhibit nuclease activity. The most active compound (1h) was further studied to deduce the mode of interaction with model serum protein, bovine serum albumin (BSA).


Assuntos
Antituberculosos/farmacologia , Cumarínicos/farmacologia , Éteres/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Oximas/farmacologia , Soroalbumina Bovina/química , Animais , Antituberculosos/síntese química , Antituberculosos/química , Bovinos , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/química , Clivagem do DNA , Relação Dose-Resposta a Droga , Éteres/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oximas/química , Relação Estrutura-Atividade , Células Vero
19.
ChemMedChem ; 13(7): 748-753, 2018 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-29409113

RESUMO

The Hedgehog (Hh) signaling pathway is critical for embryonic patterning and postembryonic tissue regeneration. Constitutive pathway activation has also been linked to human malignancies such as basal cell carcinoma (BCC) and medulloblastoma; therefore, multiple small-molecule scaffolds that inhibit Hh signaling are in development. Previously, Grundmann's alcohol, also known as the "northern region" of vitamin D3 (VD3), has been identified as a moderate Hh pathway inhibitor. In this study, isomers of Grundmann's alcohol with different orientations of the C4 hydroxy group and C3α proton were investigated to determine the optimal configuration for this hexahydroindane scaffold with respect to Hh inhibition. A series of analogues containing Grundmann's alcohol linked to a substituted phenyl or benzyl ring through an ether or thioether linker were synthesized and evaluated for their anti-Hh activity. Of these, analogue 17 ((1R,3aR,4R,7aR)-1-[(R)-1,5-dimethylhexyl]-4-(4-aminophenoxy)-7a-methyloctahydro-1H-indene) demonstrated potent anti-Hh activity in Hh-dependent BCC cells and did not activate canonical vitamin D receptor signaling, demonstrating its selective nature for the Hh signaling pathway.


Assuntos
Colecalciferol/análogos & derivados , Colecalciferol/farmacologia , Éteres/farmacologia , Proteínas Hedgehog/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Sulfetos/farmacologia , Animais , Linhagem Celular Tumoral , Colecalciferol/síntese química , Éteres/síntese química , Éteres/química , Camundongos , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Sulfetos/síntese química , Sulfetos/química
20.
Eur J Med Chem ; 144: 730-739, 2018 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-29291440

RESUMO

Multidrug resistance is a widespread problem among various diseases and cancer is no exception. We had previously described the chemo-sensitizing activity of ecdysteroid derivatives with low polarity on drug susceptible and multi-drug resistant (MDR) cancer cells. We have also shown that these molecules have a marked selectivity towards the MDR cells. Recent studies on the oximation of various steroid derivatives indicated remarkable increase in their antitumor activity, but there is no related bioactivity data on ecdysteroid oximes. In our present study, 13 novel ecdysteroid derivatives (oximes, oxime ethers and a lactam) and one known compound were synthesized from 20-hydroxyecdysone 2,3;20,22-diacetonide and fully characterized by comprehensive NMR techniques revealing their complete 1H and 13C signal assignments. The compounds exerted moderate to strong in vitro antiproliferative activity on HeLa, SiHa, MCF-7 and MDA-MB-231 cell lines. Oxime and particularly oxime ether formation strongly increased their inhibitory activity on the efflux of rhodamine 123 by P-glycoprotein (P-gp), while the new ecdysteroid lactam did not interfere with the efflux function. All compounds exerted potent chemo-sensitizing activity towards doxorubicin on a mouse lymphoma cell line and on its MDR counterpart, and, on the latter, the lactam was found the most active. Because of its MDR-selective chemo-sensitizing activity with no functional effect on P-gp, this lactam is of high potential interest as a new lead for further antitumor studies.


Assuntos
Antineoplásicos/farmacologia , Ecdisteroides/farmacologia , Éteres/farmacologia , Lactamas/farmacologia , Neoplasias/tratamento farmacológico , Nitrogênio/farmacologia , Oximas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Ecdisteroides/síntese química , Ecdisteroides/química , Éteres/síntese química , Éteres/química , Humanos , Lactamas/síntese química , Lactamas/química , Estrutura Molecular , Neoplasias/patologia , Nitrogênio/química , Oximas/síntese química , Oximas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
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