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1.
Anticancer Res ; 40(9): 5049-5057, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878793

RESUMO

BACKGROUND/AIM: Studies with acridine compounds have reported anticancer effects. Herein, we evaluated the toxicity and antitumor effect of the (E)-1'-((4-chlorobenzylidene)amino)-5'-oxo-1',5'-dihydro-10H-spiro[acridine-9,2'-pyrrole]-4'-carbonitrile (AMTAC-06), a promising anticancer spiro-acridine compound. MATERIALS AND METHODS: The toxicity of AMTAC-06 was evaluated on zebrafish and mice. Antitumor activity was assessed in Ehrlich ascites carcinoma model. Effects on angiogenesis, cytokine levels and cell cycle were also investigated. RESULTS: AMTAC-06 did not induce toxicity on zebrafish and mice (LD50 approximately 5000 mg/kg, intraperitoneally). No genotoxicity was observed on micronucleus assay. AMTAC-06 significantly reduced the total viable Ehrlich tumor cells and increased sub-G1 peak, suggesting apoptosis was triggered. Moreover, the compound significantly decreased the density of peritumoral microvessels, indicating an anti-angiogenic action, possibly dependent on the cytokine modulation (TNF-α, IL-1ß and IFN-γ). No significant toxicological effects were recorded for AMTAC-06 on tumor transplanted animals. CONCLUSION: AMTAC-06 has low toxicity and a significant antitumor activity.


Assuntos
Acridinas/farmacologia , Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Fatores Imunológicos/farmacologia , Compostos de Espiro/farmacologia , Acridinas/química , Inibidores da Angiogênese/química , Animais , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Fatores Imunológicos/química , Imunomodulação/efeitos dos fármacos , Camundongos , Estrutura Molecular , Compostos de Espiro/química , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
2.
Anesthesiology ; 133(4): 740-749, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32773684

RESUMO

The United States Food and Drug Administration is tasked with ensuring the efficacy and safety of medications marketed in the United States. One of their primary responsibilities is to approve the entry of new drugs into the marketplace, based on the drug's perceived benefit-risk relationship. The Anesthetic and Analgesic Drug Product Advisory Committee is composed of experts in anesthesiology, pain management, and biostatistics, as well as consumer and industry representatives, who meet several times annually to review new anesthetic-related drugs, those seeking new indications, and nearly every opioid-related application for approval. The following report describes noteworthy activities of this committee since 2017, as it has grappled, along with the Food and Drug Administration, to balance the benefit-risk relationships for individual patients along with the overarching public health implications of bringing additional opioids to market. All anesthesia advisory committee meetings since 2017 will be described, and six will be highlighted, each with representative considerations for potential new opioid formulations or local anesthetics.


Assuntos
Comitês Consultivos/normas , Analgésicos Opioides/química , Analgésicos/química , Anestésicos/química , Aprovação de Drogas/métodos , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Analgésicos/efeitos adversos , Analgésicos Opioides/efeitos adversos , Anestésicos/efeitos adversos , Congressos como Assunto/normas , Tomada de Decisões , Preparações de Ação Retardada/efeitos adversos , Preparações de Ação Retardada/química , Humanos , Oximorfona/efeitos adversos , Oximorfona/química , Compostos de Espiro/efeitos adversos , Compostos de Espiro/química , Tiofenos/efeitos adversos , Tiofenos/química , Estados Unidos
3.
Mol Pharmacol ; 98(4): 475-486, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32680919

RESUMO

Methadone is a synthetic opioid agonist with notoriously unique properties, such as lower abuse liability and induced relief of withdrawal symptoms and drug cravings, despite acting on the same opioid receptors triggered by classic opioids-in particular the µ-opioid receptor (MOR). Its distinct pharmacologic properties, which have recently been attributed to the preferential activation of ß-arrestin over G proteins, make methadone a standard-of-care maintenance medication for opioid addiction. Although a recent biophysical study suggests that methadone stabilizes different MOR active conformations from those stabilized by classic opioid drugs or G protein-biased agonists, how this drug modulates the conformational equilibrium of MOR and what specific active conformation of the receptor it stabilizes are unknown. Here, we report the results of submillisecond adaptive sampling molecular dynamics simulations of a predicted methadone-bound MOR complex and compare them with analogous data obtained for the classic opioid morphine and the G protein-biased ligand TRV130. The model, which is supported by existing experimental data, is analyzed using Markov state models and transfer entropy analysis to provide testable hypotheses of methadone-specific conformational dynamics and activation kinetics of MOR. SIGNIFICANCE STATEMENT: Opioid addiction has reached epidemic proportions in both industrialized and developing countries. Although methadone maintenance treatment represents an effective therapeutic approach for opioid addiction, it is not as widely used as needed. In this study, we contribute an atomic-level understanding of how methadone exerts its unique function in pursuit of more accessible treatments for opioid addiction. In particular, we present details of a methadone-specific active conformation of the µ-opioid receptor that has thus far eluded experimental structural characterization.


Assuntos
Analgésicos Opioides/farmacologia , Metadona/farmacologia , Receptores Opioides mu/química , Receptores Opioides mu/metabolismo , Compostos de Espiro/farmacologia , Tiofenos/farmacologia , Analgésicos Opioides/química , Animais , Sítios de Ligação , Entropia , Humanos , Cadeias de Markov , Metadona/química , Camundongos , Modelos Moleculares , Simulação de Dinâmica Molecular , Ligação Proteica , Conformação Proteica/efeitos dos fármacos , Compostos de Espiro/química , Tiofenos/química
4.
Chemosphere ; 256: 127019, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32417588

RESUMO

Marine and freshwater toxins contaminate water resources, shellfish and aquaculture products, causing a broad range of toxic effects in humans and animals. Different core-shell nanoparticles were tested as a new sorbent for removing marine and freshwater toxins from liquid media. Water solutions were contaminated with 20 µg/L of marine toxins and up to 50 µg/L of freshwater toxins and subsequently treated with 250 or 125 mg/L of nanoparticles. Under these conditions, carbon nanoparticles removed around 70% of saxitoxins, spirolides, and azaspiracids, and up to 38% of diarrheic shellfish poisoning toxins. In the case of freshwater toxins, the 85% of microcystin LR was eliminated; other cyclic peptide toxins were also removed in a high percentage. Marine toxins were adsorbed in the first 5 min of contact, while for freshwater toxins it was necessary 60 min to reach the maximum adsorption. Toxins were recovered by extraction from nanoparticles with different solvents. Gymnodinium catenatum, Prorocentrum lima, and Microcystis aeruginosa cultures were employed to test the ability of nanoparticles to adsorb toxins in a real environment, and the same efficacy to remove toxins was observed in these conditions. These results suggest the possibility of using the nanotechnology in the treatment of contaminated water or in chemical analysis applications.


Assuntos
Toxinas Marinhas/química , Nanoestruturas/química , Compostos de Espiro/química , Purificação da Água/métodos , Animais , Dinoflagelados , Água Doce/química , Humanos , Fenômenos Magnéticos , Toxinas Marinhas/análise , Microcistinas , Microcystis , Saxitoxina , Alimentos Marinhos/análise , Frutos do Mar/análise , Intoxicação por Frutos do Mar , Compostos de Espiro/análise
5.
Eur J Med Chem ; 194: 112240, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32248003

RESUMO

Discovery and optimization of selective liver X receptor ß (LXRß) agonists are challenging due to the high homology of LXRα and LXRß in the ligand-binding domain. There is only one different residue (Val versus Ile) at the ligand-binding pocket of LXRs. With machine learning methods, we identified pan LXR agonists with a novel scaffold (spiro[pyrrolidine-3,3'-oxindole]). Then, we figured out the mechanism of LXR isoform selectivity from co-crystal structures. Based on the mechanism and the new scaffold, LXRß selective agonists were designed and synthesized. This led to the discovery of LXRß agonists 4-7rr, 4-13 and 4-13rr with IC50 values ranging from 1.78 to 6.36 µM against glioblastoma in vitro. Treatment with 50 mg/kg/day of 4-13 for 15 days significantly reduced tumor growth using an in vivo xenograft glioblastoma model.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Glioblastoma/tratamento farmacológico , Receptores X do Fígado/agonistas , Oxindois/farmacologia , Pirrolidinas/farmacologia , Compostos de Espiro/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma/metabolismo , Células HEK293 , Humanos , Receptores X do Fígado/metabolismo , Aprendizado de Máquina , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Oxindois/síntese química , Oxindois/química , Pirrolidinas/síntese química , Pirrolidinas/química , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
6.
Nat Commun ; 11(1): 1867, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32313070

RESUMO

Plant halogenated natural products are rare and harbor various interesting bioactivities, yet the biochemical basis for the involved halogenation chemistry is unknown. While a handful of Fe(II)- and 2-oxoglutarate-dependent halogenases (2ODHs) have been found to catalyze regioselective halogenation of unactivated C-H bonds in bacteria, they remain uncharacterized in the plant kingdom. Here, we report the discovery of dechloroacutumine halogenase (DAH) from Menispermaceae plants known to produce the tetracyclic chloroalkaloid (-)-acutumine. DAH is a 2ODH of plant origin and catalyzes the terminal chlorination step in the biosynthesis of (-)-acutumine. Phylogenetic analyses reveal that DAH evolved independently in Menispermaceae plants and in bacteria, illustrating an exemplary case of parallel evolution in specialized metabolism across domains of life. We show that at the presence of azide anion, DAH also exhibits promiscuous azidation activity against dechloroacutumine. This study opens avenues for expanding plant chemodiversity through halogenation and azidation biochemistry.


Assuntos
Alcaloides/biossíntese , Compostos Ferrosos/metabolismo , Hidrolases/metabolismo , Ácidos Cetoglutáricos/metabolismo , Menispermaceae/metabolismo , Compostos de Espiro/metabolismo , Alcaloides/química , Alcaloides/genética , Bactérias/metabolismo , Biocatálise , Genes de Plantas/genética , Halogenação , Menispermaceae/embriologia , Menispermaceae/genética , Mutagênese , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Proteínas Recombinantes , Metabolismo Secundário/genética , Alinhamento de Sequência , Compostos de Espiro/química , Transcriptoma
7.
Proc Natl Acad Sci U S A ; 117(17): 9338-9348, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32284409

RESUMO

Oxidation of guanine generates several types of DNA lesions, such as 8-oxoguanine (8OG), 5-guanidinohydantoin (Gh), and spiroiminodihydantoin (Sp). These guanine-derived oxidative DNA lesions interfere with both replication and transcription. However, the molecular mechanism of transcription processing of Gh and Sp remains unknown. In this study, by combining biochemical and structural analysis, we revealed distinct transcriptional processing of these chemically related oxidized lesions: 8OG allows both error-free and error-prone bypass, whereas Gh or Sp causes strong stalling and only allows slow error-prone incorporation of purines. Our structural studies provide snapshots of how polymerase II (Pol II) is stalled by a nonbulky Gh lesion in a stepwise manner, including the initial lesion encounter, ATP binding, ATP incorporation, jammed translocation, and arrested states. We show that while Gh can form hydrogen bonds with adenosine monophosphate (AMP) during incorporation, this base pair hydrogen bonding is not sufficient to hold an ATP substrate in the addition site and is not stable during Pol II translocation after the chemistry step. Intriguingly, we reveal a unique structural reconfiguration of the Gh lesion in which the hydantoin ring rotates ∼90° and is perpendicular to the upstream base pair planes. The perpendicular hydantoin ring of Gh is stabilized by noncanonical lone pair-π and CH-π interactions, as well as hydrogen bonds. As a result, the Gh lesion, as a functional mimic of a 1,2-intrastrand crosslink, occupies canonical -1 and +1 template positions and compromises the loading of the downstream template base. Furthermore, we suggest Gh and Sp lesions are potential targets of transcription-coupled repair.


Assuntos
Guanidinas/química , Guanosina/análogos & derivados , Hidantoínas/química , RNA Polimerase II/metabolismo , Compostos de Espiro/química , Pareamento de Bases , DNA/química , DNA/metabolismo , Dano ao DNA/fisiologia , Reparo do DNA/fisiologia , Guanidinas/metabolismo , Guanina/metabolismo , Guanosina/química , Guanosina/metabolismo , Hidantoínas/metabolismo , Oxirredução , Estresse Oxidativo/fisiologia , Purinas/metabolismo , RNA Polimerase II/fisiologia , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Compostos de Espiro/metabolismo , Transcrição Genética/fisiologia , Ativação Transcricional/fisiologia
8.
J Med Chem ; 63(10): 5089-5099, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32022560

RESUMO

We have previously shown that the oral administration of the small molecule hPTHR1 agonist PCO371 and its lead compound, 1 (CH5447240) results in PTH-like calcemic and hypophostemic activity in thyroparathyroidectomized rats. However, 1 was converted to a reactive metabolite in a human liver microsome assay. In this article, we report on the modification path that led to an enhancement of PTHR1 agonistic activity and reduction in the formation of a reactive metabolite to result in a potent, selective, and orally active PTHR1 agonist 1-(3,5-dimethyl-4-(2-((4-oxo-2-(4-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)sulfonyl)ethyl)phenyl)-5,5-dimethylimidazolidine-2,4-dione (PCO371, 16c). This compound is currently being evaluated in a phase 1 clinical study for the treatment of hypoparathyroidism.


Assuntos
Imidazolidinas/administração & dosagem , Imidazolidinas/metabolismo , Receptor Tipo 1 de Hormônio Paratireóideo/agonistas , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Compostos de Espiro/administração & dosagem , Compostos de Espiro/metabolismo , Administração Oral , Animais , Feminino , Humanos , Hipoparatireoidismo/tratamento farmacológico , Hipoparatireoidismo/metabolismo , Imidazolidinas/química , Células LLC-PK1 , Ratos , Ratos Sprague-Dawley , Compostos de Espiro/química , Suínos
9.
Pharmacol Rep ; 72(2): 427-434, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32002826

RESUMO

BACKGROUND: In our previous work, spiroxatrine was taken as reference compound to develop selective NOP ligands. Therefore, several triazaspirodecanone derivatives were synthesized. Here, we verify their selectivity towards other 5-HT1 receptor subtypes and with respect to α2-AR (Adrenergic Receptors). METHODS: Binding affinities were determined on cells expressing human cloned receptors for 5-HT1A/B/D and α2A/B/C subtypes. The Ki values were determined for those with at least 50% radioligand inhibition. RESULTS: All our derivatives show a moderate affinity for α2 subtypes, spanning from 5 to 7.5 pKi values. Moreover, they show affinity values in a µM-nM range at the 5-HT1A receptor, while they are practically inactive at 5-HT1B and 5-HT1D subtypes. Compound 11, the best of the series, has a 5-HT1A pKi value of 8.43 similar to spiroxatrine but, notably, it has a 5-HT1A favorable selectivity ratio of 52, 8 and 29, respectively over α2A, α2B and α2C adrenoceptor subtypes. CONCLUSIONS: In this SAR study, a 5-HT1A selective ligand has been identified in which a tetralone moiety replaced the 1,4-benzodioxane of spiroxatrine and the methylene linker to the triazaspirodecanone portion was maintained in position 2.


Assuntos
Dioxanos/farmacologia , Descoberta de Drogas , Receptor 5-HT1A de Serotonina/metabolismo , Compostos de Espiro/farmacologia , Animais , Ligação Competitiva , Células CHO , Cricetulus , Dioxanos/química , Dioxanos/metabolismo , Humanos , Ligantes , Estrutura Molecular , Ligação Proteica , Ensaio Radioligante , Receptor 5-HT1A de Serotonina/genética , Receptores Adrenérgicos alfa 2/genética , Receptores Adrenérgicos alfa 2/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Compostos de Espiro/química , Compostos de Espiro/metabolismo , Relação Estrutura-Atividade
10.
Eur J Med Chem ; 191: 112143, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32078865

RESUMO

Herein, we communicate our recent medicinal chemistry efforts which have culminated in a series of PI3Kδ/γ dual inhibitors structurally featuring a seven-membered spirocyclic spacer. Compound 26, the most potent one among them, exhibited superior PI3Kδ inhibitory activity (IC50 = 1.0 nM) to that of the approved PI3Kδ inhibitor Idelalisib. Besides, it exerted remarkable anti-proliferative efficacy against human malignant B-cell line SU-DHL-6 with GI50 value of 33 nM. The biochemical assay against the other three class I PI3K isoforms identified compound 26 as a potent PI3Kδ/γ dual inhibitor with considerable selectivity over PI3Kα and PI3Kß. In SU-DHL-6 cells, a dramatic down-regulation of PI3K signaling was observed following compound 26-treatment at the concentration as low as 10 nM. Inspiringly, the pharmacokinetic (PK) study in Sprague-Dawley (SD) rats revealed it was orally available with a favorable bioavailability (F = 87.5%). Overall, compound 26, a promising PI3Kδ/γ dual inhibitor, has the potential to emerge as a clinical candidate for the treatment of leukocyte-mediated malignancies after extensive functional investigation.


Assuntos
Antineoplásicos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Compostos de Espiro/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Inibidores de Fosfoinositídeo-3 Quinase/química , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-Atividade
11.
Org Biomol Chem ; 18(5): 931-940, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-31922157

RESUMO

The design of glycogen phosphorylase (GP) inhibitors targeting the catalytic site of the enzyme is a promising strategy for a better control of hyperglycaemia in the context of type 2 diabetes. Glucopyranosylidene-spiro-heterocycles have been demonstrated as potent GP inhibitors, and more specifically spiro-oxathiazoles. A new synthetic route has now been elaborated through 1,3-dipolar cycloaddition of an aryl nitrile oxide to a glucono-thionolactone affording in one step the spiro-oxathiazole moiety. The thionolactone was obtained from the thermal rearrangement of a thiosulfinate precursor according to Fairbanks' protocols, although with a revisited outcome and also rationalised with DFT calculations. The 2-naphthyl substituted glucose-based spiro-oxathiazole 5h, identified as one of the most potent GP inhibitors (Ki = 160 nM against RMGPb) could be produced on the gram-scale from this strategy. Further evaluation in vitro using rat and human hepatocytes demonstrated that compound 5h is a anti-hyperglycaemic drug candidates performing slightly better than DAB used as a positive control. Investigation in Zucker fa/fa rat model in acute and subchronic assays further confirmed the potency of compound 5h since it lowered blood glucose levels by ∼36% at 30 mg kg-1 and ∼43% at 60 mg kg-1. The present study is one of the few in vivo investigations for glucose-based GP inhibitors and provides data in animal models for such drug candidates.


Assuntos
Inibidores Enzimáticos/farmacologia , Glucose/metabolismo , Glicogênio Fosforilase/antagonistas & inibidores , Hipoglicemiantes/farmacologia , Compostos de Espiro/farmacologia , Tiazóis/farmacologia , Animais , Glicemia/metabolismo , Ciclização , Teoria da Densidade Funcional , Glicogênio/metabolismo , Glicogênio Fosforilase/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Concentração Inibidora 50 , Cinética , Lactonas/síntese química , Lactonas/química , Oxirredução , Ratos Zucker , Compostos de Espiro/síntese química , Compostos de Espiro/química , Estereoisomerismo , Temperatura , Tiazóis/síntese química , Tiazóis/química
12.
Molecules ; 25(3)2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31972970

RESUMO

For the convenient introduction of simple linear/branched alkyl groups into biologically important azaspirocyclohexadienones, a practical Fe-catalyzed decarbonylative cascade spiro-cyclization of N-aryl cinnamamides with aliphatic aldehydes to provide alkylated 1-azaspiro-cyclohexadienones was developed. Aliphatic aldehydes were oxidative decarbonylated into primary, secondary and tertiary alkyl radicals conveniently and allows for the subsequent cascade construction of dual C(sp3)-C(sp3) and C=O bonds via radical addition, spirocyclization and oxidation sequence.


Assuntos
Alquilantes/química , Compostos Aza/química , Cinamatos/química , Cicloexenos/química , Ferro/química , Compostos de Espiro/química , Aldeídos/química , Alquilação , Catálise , Ciclização
13.
J Antibiot (Tokyo) ; 73(5): 290-298, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31992865

RESUMO

The emergence of antibiotic resistance necessitates not only the identification of new compounds with antimicrobial properties, but also new strategies and combination therapies to circumvent this growing problem. Here, we report synergistic activity against methicillin-resistant Staphylococcus aureus (MRSA) of the ß-lactam antibiotic oxacillin combined with 7,8-dideoxygriseorhodin C in vitro. Ongoing efforts to identify antibiotics from marine mollusk-associated bacteria resulted in the isolation of 7,8-dideoxygriseorhodin C from a Streptomyces sp. strain cultivated from a marine gastropod tissue homogenate. Despite the long history of 7,8-dideoxygriseorhodin C in the literature, the absolute configuration has never been previously reported. A comparison of measured and calculated ECD spectra resolved the configuration of the spiroketal carbon C6, and 2D ROESY NMR spectroscopy established the absolute configuration as 6s,6aS. The compound is selective against Gram-positive bacteria including MRSA and Enterococcus faecium with an MIC range of 0.125-0.5 µg ml-1. Moreover, the compound synergizes with oxacillin against MRSA as observed in the antimicrobial microdilution and time-kill assays. Simultaneous treatment of the compound with oxacillin resulted in an approximately tenfold decrease in MIC with a combination index of <0.5, indicating synergistic anti-MRSA activity.


Assuntos
Antibacterianos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Oxacilina/farmacologia , Antibacterianos/administração & dosagem , Antibacterianos/isolamento & purificação , Sinergismo Farmacológico , Enterococcus faecium/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Naftoquinonas/administração & dosagem , Naftoquinonas/química , Naftoquinonas/isolamento & purificação , Naftoquinonas/farmacologia , Oxacilina/administração & dosagem , Compostos de Espiro/administração & dosagem , Compostos de Espiro/química , Compostos de Espiro/isolamento & purificação , Compostos de Espiro/farmacologia , Streptomyces/metabolismo
14.
Eur J Med Chem ; 188: 111977, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31927313

RESUMO

a series of 2-oxospiro[indoline-3,4'-pyran]derivatives 4 and 7 were obtained in good yield under mild conditions from the one-pot reaction of indole-2,3-dione derivatives 1, appropriate methylene active nitriles 2 and ß-dicarbonyl compound 3 or 6. The newly synthesized compounds were characterized and evaluated for their in vitro antibacterial, antifungal as well as immunomodulatory activity. According to MIC values, the most potent compounds 4f, 4h, 7a, 7c, 7e, 7f, 7g, 8a, and 8c were evaluated for MBC and displayed high activity to killing pathogens with a good MBC value against norfloxacin as well as investigated against an extended panel of multidrug resistance bacteria (MDRB) and exhibited promising to moderate multidrug resistance activities, compounds 7f showed the much better than norfloxacin with higher potency results. Furthermore, the most potent compounds showed an increase in the intracellular killing activity of neutrophils which confirmed the immunostimulatory power. Eight of the nine active compounds exhibited inhibitory activities with IC50 ranged between (18.07 ± 0.18) to (27.03 ± 0.24) µM stronger than ciprofloxacin (26.43 ± 0.64 µM) for S. aureus DNA gyrase. Molecular docking was performed inside the active site of S. aureus DNA gyrase to predict the binding mode.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Sulfonatos de Arila/farmacologia , Fatores Imunológicos/farmacologia , Compostos de Espiro/farmacologia , Inibidores da Topoisomerase/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Sulfonatos de Arila/síntese química , Sulfonatos de Arila/química , DNA Girase/metabolismo , Relação Dose-Resposta a Droga , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/química
15.
Biosci Biotechnol Biochem ; 84(1): 25-30, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31516064

RESUMO

The Japanese orange fly, Bactrocera tsuneonis, infests various citrus crops. While male pheromone components accumulated in the rectal glands are well characterized for Bactrocera, but information regarding the chemical factors involved in the life cycles of B. tsuneonis remains scarce. Herein, several volatile chemicals including a γ-decalactone, (3R,4R)-3-hydroxy-4-decanolide [(3R,4R)-HD], were identified as major components, along with acetamide and spiroketals as minor components in the rectal gland complexes of male B. tsuneonis flies. The lactone (3R,4R)-HD was also identified in female rectal gland complexes. The amount of this compound in mature males was significantly higher than those observed in females and immature males. The lactone (3R,4R)-HD was detected in flies fed with sucrose only, indicating that this lactone is not derived from dietary sources during adulthood, but biosynthesized in vivo. The predominant accumulation of (3R,4R)-HD in mature males also suggests a possible role in reproductive behavior.


Assuntos
Lactonas/química , Glândula de Sal/química , Tephritidae/fisiologia , Acetamidas/síntese química , Acetamidas/química , Animais , Cromatografia Gasosa , Citrus , Dieta , Feminino , Furanos/síntese química , Furanos/química , Japão , Lactonas/síntese química , Masculino , Espectrometria de Massas , Reprodução/fisiologia , Atrativos Sexuais/química , Comportamento Sexual Animal/fisiologia , Compostos de Espiro/síntese química , Compostos de Espiro/química , Sacarose
16.
Mini Rev Med Chem ; 20(2): 152-160, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31538895

RESUMO

BACKGROUND: Spirothiazolidines are versatile synthetic scaffold possessing wide spectrum of biological interests involving potential anticancer activity. OBJECTIVE: To report the first synthesis of Bis Spiro-thiazolidine as a novel heterocyclic ring system. METHODS: One-pot three-component reaction including condensation of p-phenyllene diamine; cyclohexanone and thioglycolic acid produced Spiro-thiazolidine 4, which underwent further condensation with cyclohexanone and thioglycolic acid with equimolar ratio to introduce Bis-Spiothiazolidine 5 as the first synthesis. Also, bis spiro-thiazolidine arylidene derivatives 6-13 were synthesized by the reaction of Bis-Spiothiazolidine 5 with different aromatic benzaldehydes. RESULTS: Four compounds 13, 12, 9 and 11 have shown highly significant anticancer activity compared to Doxorubicin® (positive control) against Human liver carcinoma (HepG2) and Human Normal Retina pigmented epithelium (RPE-1) cell lines. CONCLUSION: The novel bis-spirothiazolidine deriviatives have been synthesized for the first time and showed excellent anticancer activities compare with the corresponding spirothiazolidine derivatives.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Compostos Heterocíclicos/farmacologia , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Tiazolidinas/síntese química , Tiazolidinas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Candida albicans/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Células Hep G2 , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos de Espiro/química , Relação Estrutura-Atividade , Tiazolidinas/química
17.
Nat Prod Res ; 34(19): 2802-2808, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30929454

RESUMO

Two new compounds Talaromycin A (1) and Talaromycin B (2) were isolated from a liquid culture of Talaromyces aurantiacus. The structures of 1 and 2 were elucidated by IR, MS, 1D and 2D NMR spectra and comparison of the experimental and calculated electronic circular dichroism spectra. Additional known compounds (3-6) were also isolated. These compounds were tested for monoamine oxidase, acetylcholinesterase and PI3K inhibitory activity, but showed only weak activity.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Compostos de Espiro/química , Talaromyces/química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Dicroísmo Circular , Avaliação Pré-Clínica de Medicamentos , Endófitos/química , Inibidores Enzimáticos/isolamento & purificação , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/química , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Compostos de Espiro/isolamento & purificação , Compostos de Espiro/farmacologia
18.
Eur J Med Chem ; 186: 111859, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31735574

RESUMO

The scaffold proteins prohibitins-1 and 2 (PHB1/2) play many important roles in coordinating many cell signaling pathways and represent emerging targets in cardiology and oncology. We previously reported that a family of natural products derivatives, flavaglines, binds to PHB1/2 to exert cardioprotectant and anti-cancer effects. However, flavaglines also target the initiation factor of translation eIF4A, which doesn't contribute to cardioprotection and may even induce some adverse effects. Herein, we report the development of a convenient and robust synthesis of the new PHB2 ligand 2'-phenylpyrrolidinyl-spirooxindole, and its analogues. We discovered that these compounds displays cardioprotective effect against doxorubicin mediated cardiotoxicity and uncovered the structural requirement for this activity. We identified in particular some analogues that are more cardioprotectant than flavaglines. Pull-down experiments demonstrated that these compounds bind not only to PHB2 but also PHB1. These novel PHB ligands may provide the basis for the development of new drugs candidates to protect the heart against the adverse effects of anticancer treatments.


Assuntos
Cardiotônicos/farmacologia , Descoberta de Drogas , Miócitos Cardíacos/efeitos dos fármacos , Oxindois/farmacologia , Proteínas Repressoras/antagonistas & inibidores , Compostos de Espiro/farmacologia , Apoptose/efeitos dos fármacos , Cardiotônicos/síntese química , Cardiotônicos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/antagonistas & inibidores , Doxorrubicina/farmacologia , Humanos , Ligantes , Estrutura Molecular , Miócitos Cardíacos/metabolismo , Oxindois/síntese química , Oxindois/química , Proteínas Repressoras/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-Atividade
19.
Curr Top Med Chem ; 20(2): 140-152, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31702503

RESUMO

INTRODUCTION: Structural modulation of previously identified lead spiro-ß-lactams with antimicrobial activity was carried out. OBJECTIVE: The main objective of this work was to synthesize and evaluate the biological activity of novel spiro-lactams based on previously identified lead compounds with antimicrobial activity. METHODS: The target chiral spiro-γ-lactams were synthesized through 1,3-dipolar cycloaddition reaction of a diazo-γ-lactam with electron-deficient dipolarophiles. In vitro activity against HIV and Plasmodium of a wide range of spiro-ß-lactams and spiro-γ-lactams was evaluated. Among these compounds, one derivative with good anti-HIV activity and two with promising antiplasmodial activity (IC50 < 3.5 µM) were identified. RESULTS: A novel synthetic route to chiral spiro-γ-lactams has been established. The studied ß- and γ- lactams were not cytotoxic, and three compounds with promising antimicrobial activity were identified, whose structural modulation may lead to new and more potent drugs. CONCLUSION: The designed structural modulation of biologically active spiro-ß-lactams involved the replacement of the four-membered ß-lactam ring by a five-membered γ-lactam ring. Although conformational and superimposition computational studies revealed no significant differences between ß- and γ- lactam pharmacophoric features, the studied structural modulation did not lead to compounds with a similar biological profile. The observed results suggest that the ß-lactamic core is a requirement for the activity against both HIV and Plasmodium.


Assuntos
Fármacos Anti-HIV/farmacologia , Antiprotozoários/farmacologia , HIV/efeitos dos fármacos , Lactamas/farmacologia , Plasmodium/efeitos dos fármacos , Compostos de Espiro/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Lactamas/síntese química , Lactamas/química , Testes de Sensibilidade Microbiana , Conformação Molecular , Testes de Sensibilidade Parasitária , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-Atividade
20.
Org Lett ; 22(4): 1233-1238, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-31789039

RESUMO

A gold-catalyzed dearomatization reaction of indole derivatives was realized in the presence of JohnPhosAuCl/AgOMs to afford a series of spiroindolenines in excellent yields (≤99%). In addition, when the Hantzsch ester was used as the hydrogen transfer reagent, various spiroindolines were obtained in a cascade fashion starting from readily available indole derivatives in modest to good yields (≤79%). Both reactions feature readily available substrates, mild conditions, and good functional group tolerance.


Assuntos
Ouro/química , Indóis/química , Indóis/síntese química , Compostos de Espiro/síntese química , Catálise , Estrutura Molecular , Compostos de Espiro/química , Estereoisomerismo
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