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1.
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
2.
Org Biomol Chem ; 18(11): 2051-2053, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-32141462

RESUMO

Total synthesis of isatindigotindoline C, a 3,3'-spiropyrrolidine oxindole alkaloid, is achieved in two steps using an exo-selective decarboxylative 1,3-dipolar cycloaddition as the key step. The synthesis verifies the originally assigned relative anti-stereochemistry for the bis-oxindole core of isatindigotindoline C.


Assuntos
Alcaloides Indólicos/síntese química , Reação de Cicloadição/métodos , Descarboxilação , Oxindois , Compostos de Espiro/síntese química
3.
J Med Chem ; 63(7): 3723-3736, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32134263

RESUMO

Semisynthetic artemisinins and other bioactive peroxides are best known for their powerful antimalarial activities, and they also show substantial activity against schistosomes-another hemoglobin-degrading pathogen. Building on this discovery, we now describe the initial structure-activity relationship (SAR) of antischistosomal ozonide carboxylic acids OZ418 (2) and OZ165 (3). Irrespective of lipophilicity, these ozonide weak acids have relatively low aqueous solubilities and high protein binding values. Ozonides with para-substituted carboxymethoxy and N-benzylglycine substituents had high antischistosomal efficacies. It was possible to increase solubility, decrease protein binding, and maintain the high antischistosomal activity in mice infected with juvenile and adult Schistosoma mansoni by incorporating a weak base functional group in these compounds. In some cases, adding polar functional groups and heteroatoms to the spiroadamantane substructure increased the solubility and metabolic stability, but in all cases decreased the antischistosomal activity.


Assuntos
Adamantano/uso terapêutico , Ácidos Carboxílicos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Esquistossomicidas/uso terapêutico , Compostos de Espiro/uso terapêutico , Adamantano/análogos & derivados , Adamantano/farmacocinética , Adamantano/toxicidade , Animais , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacocinética , Ácidos Carboxílicos/toxicidade , Linhagem Celular Tumoral , Feminino , Células HEK293 , Compostos Heterocíclicos com 1 Anel/síntese química , Compostos Heterocíclicos com 1 Anel/farmacocinética , Compostos Heterocíclicos com 1 Anel/toxicidade , Humanos , Camundongos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Esquistossomicidas/síntese química , Esquistossomicidas/farmacocinética , Esquistossomicidas/toxicidade , Compostos de Espiro/síntese química , Compostos de Espiro/farmacocinética , Compostos de Espiro/toxicidade , Relação Estrutura-Atividade
4.
J Med Chem ; 63(7): 3552-3562, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32073266

RESUMO

We report the discovery of a novel indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor class through the affinity selection of a previously unreported indole-based DNA-encoded library (DEL). The DEL exemplar, spiro-chromane 1, had moderate IDO1 potency but high in vivo clearance. Series optimization quickly afforded a potent, low in vivo clearance lead 11. Although amorphous 11 was highly bio-available, crystalline 11 was poorly soluble and suffered disappointingly low bio-availability because of solubility-limited absorption. A prodrug approach was deployed and proved effective in discovering the highly bio-available phosphonooxymethyl 31, which rapidly converted to 11 in vivo. Obtaining crystalline 31 proved problematic, however; thus salt screening was performed in an attempt to circumvent this obstacle and successfully delivered greatly soluble and bio-available crystalline tris-salt 32. IDO1 inhibitor 32 is characterized by a low calculated human dose, best-in-class potential, and an unusual inhibition mode by binding the IDO1 heme-free (apo) form.


Assuntos
DNA/química , Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Pró-Fármacos/farmacologia , Compostos de Espiro/farmacologia , Animais , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Eutérios , Masculino , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Compostos de Espiro/síntese química , Compostos de Espiro/farmacocinética , Relação Estrutura-Atividade
5.
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
6.
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
7.
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
8.
J Med Chem ; 63(3): 1337-1360, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31910017

RESUMO

p300 and CREB-binding protein (CBP) are ubiquitously expressed pleiotropic lysine acetyltransferases and play a key role as transcriptional co-activators that are essential for a multitude of cellular processes. Despite great importance, there is a lack of highly selective, potent, druglike p300/CBP inhibitors. Through the artificial-intelligence-assisted drug discovery pipeline and further optimization, we reported the discovery of novel, highly selective, potent small-molecule inhibitors of p300/CBP histone acetyltransferases (HAT) with desired druglike properties, exemplified by B026. Our data demonstrated that B026, with half maximal inhibitory concentration (IC50) values of 1.8 nM to p300 and 9.5 nM to CBP enzyme inhibitory activity, is the most potent, selective p300/CBP HAT inhibitor. Moreover, B026 achieves significant and dose-dependent tumor growth inhibition in an animal model of human cancer, suggesting that B026 is a highly promising p300/CBP HAT inhibitor and warrants extensive preclinical investigation as a potential clinical development candidate.


Assuntos
Antineoplásicos/uso terapêutico , Proteína de Ligação a CREB/antagonistas & inibidores , Proteína p300 Associada a E1A/antagonistas & inibidores , Inibidores Enzimáticos/uso terapêutico , Neoplasias/tratamento farmacológico , Compostos de Espiro/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Conjuntos de Dados como Assunto , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Masculino , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Redes Neurais de Computação , Ratos Sprague-Dawley , Compostos de Espiro/síntese química , Compostos de Espiro/farmacocinética , Relação Estrutura-Atividade
9.
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
10.
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
11.
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
12.
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
13.
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
14.
Molecules ; 24(22)2019 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-31744134

RESUMO

The reaction of diphenyl nitrilimine (NI) with methyl 1-methyl-allenoate yielding a spirobipyrazoline has been studied within molecular electron density theory (MEDT) at the MPWB1K/6-311G(d) computational level in dichloromethane. This reaction is a domino process that comprises two consecutive 32CA reactions with the formation of a pyrazoline intermediate. Analysis of the relative Gibbs free energies indicates that both 32CA reactions are highly regioselective, the first one being also completely chemoselective, in agreement with the experimental outcomes. The geometries of the TSs indicate that they are associated to asynchronous bond formation processes in which the shorter distance involves the C1 carbon of diphenyl NI. Despite the zwitterionic structure of diphenyl NI, the appearance of a pseudoradical structure at the beginning of the reaction path, with a very low energy cost, suggests that the 32CA reaction between diphenyl NI, a strong nucleophile, and the allenoate, a moderate electrophile, should be mechanistically considered on the borderline between pmr-type and cb-type 32CA reactions, somewhat closer to the latter.


Assuntos
Iminas/química , Modelos Teóricos , Compostos de Espiro/síntese química , Reação de Cicloadição , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Compostos de Espiro/química
15.
Chem Commun (Camb) ; 55(95): 14238-14254, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31724667

RESUMO

The spirobifluorene (SBF) fragment constitutes one of the most important scaffolds used in the design of Organic Semi-Conductors (OSCs) for organic electronics. In the last ten years, new generations of SBF positional isomers have appeared in the literature. The different positions of substitution (C1, C3 or C4) have allowed the tuning of the electronic properties of great interest for the further design of functional materials. The high potential of these new generations of organic semi-conductors in electronics has been demonstrated notably when they are used as host materials for Phosphorescent Organic Light-Emitting Diodes (OLEDs) or for Thermally Activated Delayed Fluorescence OLEDs. In the present feature article, we present these new generations of SBF compounds and the impact of positional isomerism on the electronic properties and device performance. Particularly, we show how the different structural and electronic parameters (nature of the linkages, bridge substitution and steric hindrance) drive the electrochemical and photophysical properties of SBF regioisomers and can be modulated. Such studies lay the foundation for material design for organic electronics.


Assuntos
Fluorenos/química , Compostos de Espiro/química , Eletrônica , Fluorenos/síntese química , Estrutura Molecular , Compostos de Espiro/síntese química , Estereoisomerismo
16.
Int J Mol Sci ; 20(19)2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31581457

RESUMO

The synthetic peroxides OZ78 and MT04 recently emerged as fasciocidal drug candidates. However, the effect of iron on fasciocidal activity and hepatocellular toxicity of these compounds is unknown. We investigated the in vitro fasciocidal activity and hepatocellular toxicity of OZ78 and MT04 in absence and presence of Fe(II)chloride and hemin, and conducted a toxicological study in mice. Studies were performed in comparison with the antimalarial artesunate (AS), a semisynthetic peroxide. Fasciocidal effects of OZ78 and MT04 were confirmed and enhanced by Fe2+ or hemin. In HepG2 cells, AS reduced cellular ATP and impaired membrane integrity concentration-dependently. In comparison, OZ78 or MT04 were not toxic at 100 µM and reduced the cellular ATP by 13% and 19%, respectively, but were not membrane-toxic at 500 µM. The addition of Fe2+ or hemin increased the toxicity of OZ78 and MT04 significantly. AS inhibited complex I, II, and IV of the mitochondrial electron transport chain, and MT04 impaired complex I and II, whereas OZ78 was not toxic. All three compounds increased cellular reactive oxygen species (ROS) concentration-dependently, with a further increase by Fe2+ or hemin. Mice treated orally with up to 800 mg OZ78, or MT04 showed no relevant hepatotoxicity. In conclusion, we confirmed fasciocidal activity of OZ78 and MT04, which was increased by Fe2+ or hemin. OZ78 and MT04 were toxic to HepG2 cells, which was explained by mitochondrial damage associated with ROS generation in the presence of iron. No relevant hepatotoxicity was observed in mice in vivo, possibly due to limited exposure and/or high antioxidative hepatic capacity.


Assuntos
Adamantano/análogos & derivados , Fasciola hepatica/efeitos dos fármacos , Fasciola hepatica/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Ferro/metabolismo , Compostos de Espiro/farmacologia , Adamantano/síntese química , Adamantano/química , Adamantano/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Cromatografia Líquida , Células Hep G2 , Humanos , Ferro/farmacologia , Microssomos Hepáticos/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/química , Espectrometria de Massas em Tandem
17.
J Org Chem ; 84(19): 12532-12541, 2019 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-31525925

RESUMO

Pharmaceutically attractive methylene lactone- and methylene lactam-based spiro compounds have been synthesized by employing amido-functionalized γ-hydroxylactam as a common intermediate. Development of a new route for bifurcated synthesis of two types of N,O-spiro compounds was accomplished by treatment of the intermediate under acidic conditions, leading to potent cytotoxic methylene lactone-based spiro compounds. New methylene lactam-based N,N-spiro compounds could be delivered via N-tert-butyloxycarbonyl protection of the terminal amide moiety of the intermediate followed by lactam cyclization under basic conditions.


Assuntos
Antineoplásicos/farmacologia , Lactamas/farmacologia , Lactonas/farmacologia , Compostos de Espiro/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Lactamas/química , Lactonas/química , Camundongos , Modelos Moleculares , Estrutura Molecular , Compostos de Espiro/síntese química , Compostos de Espiro/química
18.
Molecules ; 24(17)2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31480760

RESUMO

A synthetic approach to a new group of stable chiral C2-symmetric diimines with the 4,5-diazafluorene core has been developed based on condensation of dipinodiazafluorene with aromatic diamines. The chemical structures of new compounds were proven by spectroscopic methods and X-ray crystallography. All the compounds form solvates with organic solvents (chloroform, benzene, 1,4-dioxane) and water. Specific spectral data of the new compounds are explained using calculated data (DFT). Diimines of the pinodiazafluorene series give colored reactions with transition metal ions and can be regarded as prospective polydentate ligands with interesting luminescent and chiroptical properties.


Assuntos
Fluorenos/química , Iminas/química , Cristalografia por Raios X , Iminas/síntese química , Luminescência , Conformação Molecular , Compostos de Espiro/síntese química , Compostos de Espiro/química , Estereoisomerismo , Temperatura
19.
Anal Chim Acta ; 1082: 116-125, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31472700

RESUMO

A novel six-membered rhodamine-based fluorescent probe (6G-ClO) was developed from 2-formyl rhodamine (6G-CHO) and used for hypochlorite detection in water and HUVEC cells. Different from planar penta cycle of rhodamine spirolactam, there was a twist six-membered spirocyclic hydrazone in 6G-ClO optimized by Gaussian software at DFT/B3LYP/6-31G(d) level. The high selectivity, high sensitivity and fast response of 6G-ClO towards ClO- would be attributed to the twist six-membered spirocycle. Test-strip prepared with 6G-ClO was successfully used to semi-quantitatively indicate the concentration of ClO- in water. 6G-ClO can also quantitatively detect the concentration of ClO- in tap water and swimming pool water. The detection limit of 6G-ClO was as low as 12 nM. The co-localization staining of HUVEC cells further verified that 6G-ClO could specifically accumulate in lysosomes and capture exogenous/endogenous ClO- in living lysosomes. 6G-ClO would be a practical probe for real-time monitoring of ClO- in the biological and real water samples.


Assuntos
Corantes Fluorescentes/química , Ácido Hipocloroso/análise , Lisossomos/química , Rodaminas/química , Compostos de Espiro/química , Poluentes Químicos da Água/análise , Corantes Fluorescentes/síntese química , Células Endoteliais da Veia Umbilical Humana , Humanos , Ácido Hipocloroso/química , Limite de Detecção , Microscopia de Fluorescência/métodos , Rodaminas/síntese química , Espectrometria de Fluorescência/métodos , Compostos de Espiro/síntese química , Poluentes Químicos da Água/química
20.
Bioorg Chem ; 92: 103210, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31473472

RESUMO

A novel series of 4-oxo-spirochromane bearing primary sulfonamide group were synthetized as Carbonic Anhydrase inhibitors (CAIs) and tested for their management of neuropathic pain. Indeed, CAs have been recently validated as novel therapeutic targets in neuropathic pain. All compounds, here reported, showed strong activity against hCA II and hCA VII with KI values in the low or sub-nanomolar range. Two compounds (6d and 6l) showed good neuropathic pain attenuating effects and longer duration than drug reference acetazolamide in an animal model of oxaliplatin induced neuropathy.


Assuntos
Analgésicos/farmacologia , Anidrase Carbônica II/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Neuralgia/tratamento farmacológico , Compostos de Espiro/farmacologia , Sulfonamidas/farmacologia , Analgésicos/síntese química , Analgésicos/química , Animais , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Estrutura Molecular , Neuralgia/induzido quimicamente , Oxaliplatina/administração & dosagem , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
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