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1.
Chem Commun (Camb) ; 55(97): 14570-14573, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31660550

RESUMO

Facile synthesis of benzofuranone was achieved through a metal-free, one-pot intermolecular condensation between α-hydroxy aryl ketones and resorcinol derivatives. A library of 20 compounds with moderate to good overall yields was prepared. These compounds showed strong binding toward estrogen receptors along with good selectivity for ERß (>190-fold over ERα). Anti-proliferative activity on DU-145, U-87, and MCF-7 cells gave inhibition IC50 values in the low µM range, which suggested the promising potential therapeutic applications of these new classes of benzofuranones.


Assuntos
Antineoplásicos/farmacologia , Benzofuranos/química , Benzofuranos/farmacologia , Moduladores de Receptor Estrogênico/síntese química , Moduladores de Receptor Estrogênico/farmacologia , Receptor beta de Estrogênio/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Benzofuranos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Moduladores de Receptor Estrogênico/química , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/agonistas , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
2.
J Agric Food Chem ; 67(34): 9630-9642, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31365255

RESUMO

Six series of (+)-usnic acid derivatives were synthesized. The IC50 values of these compounds were determined in T. gondii infected HeLa cells (µM) and in HeLa cells (µM), and their selectivity indexes (SI) were calculated. In vitro, most of the derivatives tested in this study exhibited more anti activity than that of the parent compound (+)-usnic acid and the positive control drugs. Among these derivatives, methyl (E)-(1-(6-acetyl-7,9-dihydroxy-8,9b-dimethyl-1,3-dioxo-3,9b-dihydrodibenzo[b,d]furan-2(1H)-ylidene)ethyl)phenylalaninate (D3) showed the most effective anti-T. gondii activity (selectivity >2.77). In comparison with the clinically used positive control drugs sulfadiazine (selectivity 1.15), pyrimethamine (selectivity 0.89), spiramycin (selectivity 0.72), and the lead compound (+)-usnic acid (selectivity 0.96), D3 showed better results in vitro. Furthermore, D3 and (E)-6-acetyl-7,9-dihydroxy-8,9b-dimethyl-2-(1-(quinolin-6-ylamino)ethylidene)dibenzo[b,d]furan-1,3(2H,9bH)-dione (F3) had greater inhibitory effects on T. gondii (inhibition rates 76.0% and 64.6%) in vivo in comparison to spiramycin (inhibition rate 55.2%); in the peritoneal cavity of mice, the number of tachyzoites was significantly reduced (p < 0.001) in vivo. Additionally, some biochemical parameters were measured and spleen indexes were comprehensively evaluated, and the results indicated that mice treated with both compound D3 and compound F3 showed reduced hepatotoxicity and significantly enhanced antioxidative effects in comparison to the normal group. Granuloma and cyst formation were effected by the inhibition of compound D3 and compound F3 in liver sections. Overall, these results indicated that D3 and F3 for use as anti-T. gondii agents are promising lead compounds.


Assuntos
Antiprotozoários/administração & dosagem , Benzofuranos/administração & dosagem , Toxoplasma/efeitos dos fármacos , Toxoplasmose/tratamento farmacológico , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Benzofuranos/síntese química , Benzofuranos/química , Avaliação Pré-Clínica de Medicamentos , Feminino , Células HeLa , Humanos , Camundongos , Estrutura Molecular , Toxoplasma/crescimento & desenvolvimento , Toxoplasmose/parasitologia
3.
Molecules ; 24(13)2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31261939

RESUMO

Breast cancer is considered the most common and deadly cancer among women worldwide. Nanomedicine has become extremely attractive in the field of cancer treatment. Due to the high surface to volume ratio and other unique properties, nanomaterials can be specifically targeted to certain cells and tissues to interact with the living systems. The strategic planning of this study is based on using the nanoprecipitation method to prepare nanoparticles BZP-NPs (3.8-5.7 nm) of the previously prepared benzofuran-pyrazole compound (IV) BZP which showed promising cytotoxic activity. The capacity of BZP and BZP-NPs to suppress the growth of human breast tumor MCF-7 and MDA-MB-231 cells was evaluated using MTT assay. The IC50 doses of BZP and BZP-NPs targeting normal breast cells MCF-12A exceeded those targeting the cancer cells by >1000-fold, demonstrating their reasonable safety profiles in normal cells. Furthermore, cell cycle analysis, apoptosis induction detection, assessment of p53, Bcl-2, caspase-3, and PARP-1 levels of BZP and its nano-sized-BZP-NPs particles were also evaluated. Although the obtained results were in the favor of compound IV in its normal-sized particles, BZP-NPs appeared as a hit compound which showed improved cytotoxicity against the tested human breast cancer cells associated with the induction of pre-G1 apoptosis as well as cell cycle arrest at G2/M phase. The increase in caspase-3 level, upregulation of p53, and downregulation of Bcl-2 protein expression levels confirmed apoptosis. Furthermore, ELISA results exhibited that BZP-NPs produced a more favorable impact as a PARP-1 enzyme inhibitor than the parent BZP.


Assuntos
Benzofuranos/síntese química , Neoplasias da Mama/enzimologia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , Pirazóis/síntese química , Benzofuranos/química , Benzofuranos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Difusão Dinâmica da Luz , Feminino , Humanos , Células MCF-7 , Microscopia Eletrônica de Transmissão , Nanopartículas , Tamanho da Partícula , Inibidores de Poli(ADP-Ribose) Polimerases/química , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Pirazóis/química , Pirazóis/farmacologia
4.
Molecules ; 24(11)2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151186

RESUMO

Two 2,3-disubstituted benzofurans (1 and 2), analogs of gamma-aminobutyric acid (GABA), were synthesized to obtain their 2,3-dihydro derivatives from the Pd/C-driven catalytic reduction of the double bond in the furanoid ring. The synthesis produced surprising by-products. Therefore, theoretical calculations of global and local reactivity were performed based on Pearson's hard and soft acids and bases (HSAB) principle to understand the regioselectivity that occurred in the reduction of the olefinic carbons of the compounds. Local electrophilicity (ωk) was the most useful parameter for explaining the selectivity of the polar reactions. This local parameter was defined with the condensed Fukui function and redefined with the electrophilic (Pk+) Parr function. The similar patterns of both resulting sets of values helped to demonstrate the electrophilic behavior (soft acid) of the olefinic carbons in these compounds. The theoretical calculations, nuclear magnetic resonance, and resonance hybrids showed the moieties in each compound that are most susceptible to reduction.


Assuntos
Benzofuranos/química , Modelos Químicos , Oxirredução , Teoria Quântica , Benzofuranos/síntese química , Catálise , Técnicas de Química Sintética , Espectroscopia de Ressonância Magnética , Estrutura Molecular
5.
Nat Commun ; 10(1): 2507, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175289

RESUMO

(‒)-Morphine, which is selected as an essential medicine by World Health Organization, is widely applied in the treatment of the pain-related diseases. Due to its synthetically challenging molecular architecture and important clinical role, extensive synthetic studies of morphine-type alkaloids have been conducted. However, catalytic asymmetric total synthesis of (‒)-morphine remains a long-standing challenge. Here, we disclose an efficient enantioselective total synthesis of (‒)-morphine in a longest linear sequence of 16 steps. The key transformation features a highly enantioselective Robinson annulation enabled by our spiro-pyrrolidine catalyst to rapidly construct the densely functionalized cis-hydrodibenzofuran framework containing vicinal stereocenters with an all-carbon quaternary center. This asymmetric approach provides an alternative strategy for the synthesis of (‒)-morphine and its analogues.


Assuntos
Analgésicos Opioides/síntese química , Morfina/síntese química , Benzofuranos/síntese química , Carbono , Estereoisomerismo
6.
Eur J Med Chem ; 178: 243-258, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31185414

RESUMO

To address the multifactorial nature of Alzheimer's Disease (AD), a multi-target-directed ligand approach was herein developed. As a follow-up of our previous studies, a small library of newly designed 2-arylbenzofuran derivatives was evaluated towards cholinesterases and cannabinoid receptors. The two most promising compounds, 8 and 10, were then assessed for their neuroprotective activity and for their ability to modulate the microglial phenotype. Compound 8 emerged as able to fight AD from several directions: it restored the cholinergic system by inhibiting butyrylcholinesterase, showed neuroprotective activity against Aß1-42 oligomers, was a potent and selective CB2 ligand and had immunomodulatory effects, switching microglia from the pro-inflammatory M1 to the neuroprotective M2 phenotype. Derivative 10 was a potent CB2 inverse agonist with promising immunomodulatory properties and could be considered as a tool for investigating the role of CB2 receptors and for developing potential immunomodulating drugs addressing the endocannabinoid system.


Assuntos
Benzofuranos/farmacologia , Inibidores da Colinesterase/farmacologia , Fatores Imunológicos/farmacologia , Fármacos Neuroprotetores/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Benzofuranos/síntese química , Benzofuranos/química , Benzofuranos/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Células CHO , Domínio Catalítico , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Cricetulus , Desenho de Drogas , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Fatores Imunológicos/metabolismo , Camundongos , Microglia/efeitos dos fármacos , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fragmentos de Peptídeos/antagonistas & inibidores , Ligação Proteica , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo
7.
Molecules ; 24(11)2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31212606

RESUMO

Reported here is the direct synthesis of naphthofurans and benzofurans from readily available phenols and α-haloketones promoted by titanium tetrachloride which combines Friedel-Crafts-like alkylation and intramolecular cyclodehydration into one step. This simple protocol allows for the formation of a variety of high value naphthofurans and benzofurans within which a series of cyclic and acyclic groups are readily incorporated. This process demonstrates the advantages of high levels of regioselectivity, broad substrate scope, and moderate to excellent yields.


Assuntos
Benzofuranos/síntese química , Cetonas/química , Fenóis/química , Benzofuranos/química , Técnicas de Química Sintética , Espectroscopia de Ressonância Magnética , Estrutura Molecular
8.
Eur J Med Chem ; 177: 1-11, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31128433

RESUMO

Cannabinoids as THC and the CB1 allosteric modulator CBD were reported to have antiproliferative activities with no reports for other CB1 allosteric modulators as the 5-chloroindole-2-carboxamide derivatives and their furan congeners. Based on the antiproliferative activity of two 5-chlorobenzofuran-2-carboxamide allosteric CB1 modulators, a series of novel derivatives was designed and synthesized. The synthesized compounds were tested in a cell viability assay using human mammary gland epithelial cell line (MCF-10A) where all the compounds exhibited no cytotoxic effects and more than 85% cell viability at a concentration of 50 µM. Some derivatives showed good antiproliferative activities against tumor cells as compounds 8, 15, 21 and 22. The most active compound 15 showed equipotent activity to doxorubicin. Compounds 7, 9, 15, 16, 21 and 22 increased the level of active caspase 3 by 4-8 folds, compared to the control cells in MCF-7 cell line and doxorubicin as a reference drug. Compounds 15 and 21, the most activecaspase-3 inducers, increase the levels of caspase 8 and 9 indicating activation of both intrinsic and extrinsic pathways and showed potent induction of Bax, down-regulation of Bcl-2 protein levels and over-expression of Cytochrome C levels in MCF-7 cell lines. Compound 15 exhibited cell cycle arrest at the Pre-G1 and G2/M phases in the cell cycle analysis of MCF-7 cell line. The drug Likeness profile of the synthesized compounds showed that all the compounds were predicted to have high oral absorption complying with different pharmacokinetics filters.


Assuntos
Antineoplásicos/farmacologia , Benzofuranos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Benzofuranos/síntese química , Benzofuranos/química , Benzofuranos/farmacocinética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Estrutura Molecular , Receptor CB1 de Canabinoide , Relação Estrutura-Atividade
9.
Molecules ; 24(8)2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-31003438

RESUMO

The results of our previous research indicated that some derivatives of benzofurans, particularly halogeno-derivatives, are selectively toxic towards human leukemia cells. Continuing our work with this group of compounds we here report new data on the synthesis as well as regarding the physico-chemical and biological characterization of fourteen new derivatives of benzofurans, including six brominated compounds. The structures of all new compounds were established by spectroscopic methods (1H- and, 13C-NMR, ESI MS), and elemental analyses. Their cytotoxicity was evaluated against K562 (leukemia), MOLT-4 (leukemia), HeLa (cervix carcinoma), and normal cells (HUVEC). Five compounds (1c, 1e, 2d, 3a, 3d) showed significant cytotoxic activity against all tested cell lines and selectivity for cancer cell lines. The SAR analysis (structure-activity relationship analysis) indicated that the presence of bromine introduced to a methyl or acetyl group that was attached to the benzofuran system increased their cytotoxicity both in normal and cancer cells.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzofuranos/síntese química , Benzofuranos/farmacologia , Antineoplásicos/química , Benzofuranos/química , Caspase 3/metabolismo , Caspase 7/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , DNA/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Concentração Inibidora 50
10.
ACS Comb Sci ; 21(5): 408-416, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-30925043

RESUMO

A regiospecific synthesis of naphtho[2,1- b]benzofurans with a substituent at the C6 position was achieved via intramolecular 6-endo-dig electrophilic cyclization under acidic conditions to construct the central aromatic C ring. Screening of the synthesized compounds using a high-content imaging system enabled us to discover novel dual state emissive compounds 2{ 1,6}, 2{ 1,8}, and 2{ 4,3}, which are highly emissive with blue emission in their solid states as well as in solution states in most solvents. In addition, the compounds 2{ 4,3}, 2{ 4,12}, and 2{ 5,13} were found to be the most cell permeable in HeLa cells for live cell imaging with negligible phototoxicity.


Assuntos
Benzofuranos/síntese química , Corantes Fluorescentes/síntese química , Naftóis/química , Permeabilidade da Membrana Celular , Ciclização , Células HeLa , Humanos , Células MCF-7 , Estrutura Molecular , Imagem Óptica
11.
Molecules ; 24(4)2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30823615

RESUMO

Phthalides and α,ß-butenolides are two related classes of oxygenated heterocycles with a wide range of biological activities. An innovative strategy to prepare these compounds is based on C-H bond functionalization reactions, in which two simple, unfunctionalized molecules are coupled together with cleavage of a C-H bond and formation of a C-X bond (X=C or heteroatom). This paper reviews the methods for the synthesis of phthalides and α,ß-butenolides by C-H bond functionalization from non-halogenated starting materials. Over 30 methods are reported, mostly developed during the past ten years.


Assuntos
4-Butirolactona/análogos & derivados , Benzofuranos/síntese química , Complexos de Coordenação/química , Elementos de Transição/química , 4-Butirolactona/síntese química , Catálise , Reação de Cicloadição , Estrutura Molecular , Oxirredução
12.
Bioorg Med Chem Lett ; 29(6): 806-810, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30709651

RESUMO

A series of novel 2-benzoylbenzofuran derivatives possessing piperazine linker have been prepared, and their in vitro anticancer activity against a panel of human tumor cell lines by MTT assay were evaluated. The results demonstrated that tertiary amine derivatives exhibited better cytotoxic activity, and SAR study revealed that electron-donating substituents on the phenyl ring of the derivatization functionality contributed to potent anticancer activities. Among them, compounds 6, 9, 11, 18, 23 and 25 displayed both better anti-tumor activity and lower cytotoxic effect on human normal liver cell L02. Further apoptosis analysis showed that compound 18 significantly induced apoptosis in A549 cell, which was considered as the most potent anticancer agent.


Assuntos
Antineoplásicos/farmacologia , Benzofuranos/farmacologia , Piperazinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Benzofuranos/síntese química , Benzofuranos/toxicidade , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/toxicidade , Relação Estrutura-Atividade
13.
Org Lett ; 21(6): 1583-1587, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30799624

RESUMO

A pair of enantiomeric triketone-phloroglucinol hybrids, (+)- and (-)-myrtuspirone A (1), featuring an unprecedented 3-isopropyl-3 H-spiro[benzofuran-2,1'-cyclohexane] backbone, were isolated from the leaves of Myrtus communis. The absolute configuration of each enantiomer of 1 was determined by X-ray diffraction and chemical calculations. Furthermore, the gram-scale total syntheses of (±)-1 and (-)-1 were conducted in four steps using a Michael- N-iodosuccinimide (NIS)-mediated (3 + 2)-annulation reaction. Both (+)- and (-)-1 exhibited antibacterial activities against Gram-positive bacteria including multidrug-resistant strains.


Assuntos
Antibacterianos , Benzofuranos , Cicloexanos/química , Bactérias Gram-Positivas/efeitos dos fármacos , Myrtus/química , Folhas de Planta/química , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Benzofuranos/síntese química , Benzofuranos/química , Benzofuranos/farmacologia , Estrutura Molecular , Floroglucinol/química , Estereoisomerismo
14.
Med Chem ; 15(1): 77-86, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29792150

RESUMO

BACKGROUND: Benzofurans are heterocyclic compounds with neurotropic activity. Some have been developed for the treatment of acute and degenerative neuronal injuries. OBJECTIVE: The study aimed to evaluate the in silico binding of some promising benzofurans on the GABA receptors, and the in vivo neurotropic activity of benzofuran analogues (BZF 6-10) of gamma-aminobutyric acid (GABA) on a seizure model. METHODS: The ligands with the best physicochemical attributes were docked on two GABA receptors (the alpha-1 subunit of GABAA-R and GBR1 subunit of GABAB-R). Selected benzofuran derivatives were synthesized by a multistep procedure and characterized. To examine the neurotropic effects, mice were pretreated with different concentrations of the compounds prior to PTZ- or 4- AP-induced seizures. We assessed acute toxicity, motor behavior, and the effects on seizures. RESULTS: The tested ligands that complied with Lipinski's rule of five were tested in silico with GABAA-R (ΔG = -5.51 to -5.84 kcal/mol) at the allosteric site for benzodiazepines. They bound to a similar cluster of residues as the reference compound (gaboxadol, ΔG = -5.51 kcal/mol). Synthesis was achieved with good overall yields (42-9.7%). Two compounds were selected for biological tests (BZF-7 and rac-BZF-10) on a mouse model of seizures, induced by pentylenetetrazol (PTZ) or 4-aminopyridine (4-AP). PTZ-induced seizures are associated with GABA receptors, and those 4-AP-induced with the blockage of the delayed rectifier-type potassium channel, which promotes the release of the NMDA-sensitive glutamatergic ionotropic receptor and other neurotransmitters. The biological assays demonstrated that BZF-7 and rac-BZF-10 do not protect against seizures. Indeed, BZF-7 increased the number of PTZ-induced seizures and decreased latency time. The 4-AP model apparently showed a potentiation of seizure effects after administration of the BZF-analogues, evidenced by the incidence and severity of the seizures and reduced latency time. CONCLUSION: The results suggest that the test compounds are GABAergic antagonists with stimulatory activity on the CNS.


Assuntos
Benzofuranos/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Antagonistas de Receptores de GABA-B/farmacologia , Animais , Benzofuranos/síntese química , Benzofuranos/química , Benzofuranos/toxicidade , Estimulantes do Sistema Nervoso Central/síntese química , Estimulantes do Sistema Nervoso Central/química , Estimulantes do Sistema Nervoso Central/toxicidade , Antagonistas de Receptores de GABA-A/síntese química , Antagonistas de Receptores de GABA-A/química , Antagonistas de Receptores de GABA-A/toxicidade , Antagonistas de Receptores de GABA-B/síntese química , Antagonistas de Receptores de GABA-B/química , Antagonistas de Receptores de GABA-B/toxicidade , Humanos , Ligantes , Masculino , Camundongos , Simulação de Acoplamento Molecular , Receptores de GABA-A/química , Receptores de GABA-B/química
15.
Bioorg Med Chem ; 27(1): 116-124, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30503410

RESUMO

BMS-986120 is a PAR4 antagonist that is being investigated as an antiplatelet agent in phase I clinical trial. An improved synthesis of BMS-986120 has been developed. Based on the novel synthetic approach to BMS-986120, a series of deuterated derivatives of BMS-986120 have been synthesized and biologically evaluated to search for more potent antiplatelet agents. The in vitro antiplatelet assay by turbidimetry demonstrated that PC-2 and PC-6 had IC50 values of 6.30 nM and 6.97 nM, respectively, versus BMS-986120 with an IC50 of 7.80 nM. The result of in vitro metabolic stability study showed that all of the deuterated compounds had similar half-life (T1/2) and intrinsic clearance (Clint) in comparison with BMS-986120. Further probing the metabolic profile of BMS-986120 is worth being conducted.


Assuntos
Benzofuranos/farmacologia , Imidazóis/farmacologia , Morfolinas/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Receptores de Trombina/antagonistas & inibidores , Tiazóis/farmacologia , Animais , Benzofuranos/síntese química , Benzofuranos/química , Plaquetas/efeitos dos fármacos , Deutério , Estabilidade de Medicamentos , Humanos , Imidazóis/síntese química , Imidazóis/química , Masculino , Camundongos Endogâmicos ICR , Microssomos Hepáticos/metabolismo , Morfolinas/síntese química , Morfolinas/química , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/síntese química , Inibidores da Agregação de Plaquetas/química , Tiazóis/síntese química , Tiazóis/química
16.
Bioorg Med Chem Lett ; 29(1): 66-72, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30455151

RESUMO

A series of novel Benzofuran-tetrazole derivatives were successfully synthesised by integrating multicomponent Ugi-azide reaction with the molecular hybridization approach. Interestingly, a number of synthesized derivatives (5c, 5d, 5i, 5l, 5q and 5s) exhibited significant reduction of aggregation of "human" amyloid beta peptide, expressing on transgenic Caenorhabditis elegans (C. elegans) strain CL4176. Further, in silico docking results have evidenced the exquisite interaction of active compounds with the help of TcAChE-E2020 complex. These findings underscore the potential of these hybrids as lead molecules against Alzheimers's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Benzofuranos/farmacologia , Inibidores da Colinesterase/farmacologia , Simulação de Dinâmica Molecular , Tetrazóis/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/microbiologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Benzofuranos/síntese química , Benzofuranos/química , Caenorhabditis elegans/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Agregados Proteicos/efeitos dos fármacos , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/química
17.
Nat Prod Rep ; 36(4): 666-690, 2019 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-30488047

RESUMO

Covering: 2000 to 2018 Natural products containing the 2,3-dihydrobenzofuran (2,3-DHB) skeleton have been the focus of a substantial number of synthetic studies since 2000. Herein, we review the total syntheses of decursivine, serotobenine, lithospermic acid, linderol A, bisabosqual A, pterocarpans, conocarpan, heliannuols, and some resveratrol oligomers, with emphasis on the synthetic strategies employed.


Assuntos
Benzofuranos/química , Produtos Biológicos/síntese química , Benzofuranos/síntese química , Depsídeos/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Alcaloides Indólicos/síntese química , Indóis/síntese química , Estrutura Molecular
18.
Anticancer Agents Med Chem ; 19(3): 375-388, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30465514

RESUMO

BACKGROUND: Novel derivatives of benzo[b]furan were found to be highly toxic towards human chronic myelogenous (K562), acute myelogenous (HL-60) and acute lymphoblastic (MOLT-4) leukemia cells. OBJECTIVE: The objective was the characterization of the biological activity of novel benzofurans (influence on apoptosis, mitogen-activated protein kinases and on the cell cycle). Cellular protein(s) targeted by test benzofurans and mechanism of action were identified. METHODS: The methods utilized in the study were chemical synthesis, fluorescence assays, flow cytometry, gene expression by DNA microarray and real-time RT-PCR, western blotting, cytotoxicity assays, pull-down assay, mass spectroscopy, in vitro polymerization of tubulin, molecular docking. RESULTS: 1,1'-[3-(bromomethyl)-5,6- dimethoxy-1-benzofuran-2,7-diyldiethanone (1) and methyl 4-bromo-6- (dibromoacetyl)-5-hydroxy-2-methyl-1-benzofuran-3-carboxylate (2) induced apoptosis in K562 and MOLT-4 cells. The profiling of gene expression revealed that 1 and 2 increased the expression of proapoptotic genes involved in both receptor (TNFRSF 10A, TNFRSF 10B, CASP8) and mitochondrial (BAX, BID, NOXA, APAF1) pathways of apoptosis. Test benzo[b]furans activated c-Jun N-terminal kinase (JNK) and p38 kinase in K562 cells. Tubulin was identified as a protein target for benzo[b]furans in pull-down experiments with biotinylated 2. Test benzo[b]furans inhibited polymerization of tubulin monomers in vitro, decreased the level of cellular microtubules and arrested cells in a G2/M phase. Molecular docking suggests that benzo[b]furans 1 and 2 bind to tubulin via colchicine binding pocket and the complex is stabilized mainly by hydrophobic interactions. CONCLUSION: Novel benzo[b]furans with anti-microtubule activity were identified. They induce apoptosis in cancer cells and cause G2/M cell cycle arrest. Biological activity of 1 and 2 makes them potential lead compounds for development as anticancer drugs.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Benzofuranos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Moduladores de Tubulina/farmacologia , Regulação para Cima/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Benzofuranos/síntese química , Benzofuranos/química , Divisão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fase G2/efeitos dos fármacos , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
19.
Eur J Med Chem ; 162: 543-554, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30472602

RESUMO

The transcription factor STAT3 is an attractive target for a variety of cancers therapy. Napabucasin, applied in phase III clinical trials for the treatment of a variety of cancers, was regarded as one of the most promising anticancer drug by targeting STAT3. Herein, a novel series of napabucasin derivatives were designed and synthesized, which presented a potent inhibitory activity on a variety of cancers cells. Among the derivatives compound 8q exhibited potent inhibitory activity on U251, HepG2, HT29 and CT26 cells with the IC50 values of 0.22, 0.49, 0.07 and 0.14 µM, respectively, which was over 10-fold more potent than napabucasin. Treatment with compound 8q decreased protein expression level of total STAT3 and p-STAT3Y705in vitro. The binding of compound 8q with STAT3 were further validated by electrophoretic mobility shift assay and surface plasmon resonance analysis. Compound 8q has a KD of 110.2 nM for full-length STAT3 recombinant protein. Moreover, the aqueous solubility of 8q was over 4.5-fold than that of napabucasin. In addition, compound 8qin vivo significantly reduced tumor growth compared to untreated mice, and exhibited good safety profile, indicating its great potential as an efficacious drug candidate for oncotherapy.


Assuntos
Benzofuranos/síntese química , Naftoquinonas/síntese química , Fator de Transcrição STAT3/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzofuranos/química , Benzofuranos/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Camundongos , Naftoquinonas/química , Naftoquinonas/farmacologia , Neoplasias/tratamento farmacológico , Ligação Proteica , Solubilidade , Relação Estrutura-Atividade
20.
Nat Prod Res ; 33(11): 1617-1623, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29376428

RESUMO

A novel class of benzofuran derivatives is prepared from the isocyanide-based MCR, euparin and aldehydes in the presence of ZnO-nanorods as a catalyst in excellent yields at room temperature under solvent-free conditions as a green reaction medium. Also, the antioxidant activities of some synthesised compounds such as 4a, 4b, 10a and 10b were evaluated by DPPH radical scavenging and ferric reduction activity potential (FRAP) assays. Compound 10b, was shown moderate radical scavenging activity and very good reducing activity compared to standards (BHT and TBHQ).


Assuntos
Antioxidantes/farmacologia , Benzofuranos/síntese química , Benzofuranos/farmacologia , Petasites/química , Antioxidantes/síntese química , Benzofuranos/química , Avaliação Pré-Clínica de Medicamentos/métodos , Depuradores de Radicais Livres/síntese química , Depuradores de Radicais Livres/farmacologia , Química Verde , Ferro/química , Óxido de Zinco/química
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