RESUMO
In order to investigate potential therapeutically agents, novel products of Biginelli reaction (4a-l) were synthesized and exposed to cytotoxic and caspase activities, angiogenesis, cell cycle distribution, gene and microRNA expression levels, lipophilicity assessment and docking study. Among the twelve novel compounds (4a-l) evaluated for the cytotoxic activity, five of them (4c, 4d, 4f, 4k and 4l) that showed excellent activity on the tested cell lines (HeLa, LS174 and A549) were selected for further evaluation. Interestingly, compound 4f has up to three times higher selectivity index (SI) towards cancer cells than cisplatin (on HeLa, LS174 and A549 SIâ¯=â¯18.2, 13.5 and 11.2, respectively). The obtained results from cell cycle distribution and caspase activity indicate that tested compounds (4c, 4d, 4f, 4k and 4l) promoted caspase-9 activation, implicated in the intrinsic pathway of apoptosis. Lipophilicity of 4a-l was determinate by using reversed-phase high-performance liquid chromatography.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Caspase 9/metabolismo , Descoberta de Drogas , MicroRNAs/antagonistas & inibidores , Simulação de Acoplamento Molecular , Neovascularização Patológica/tratamento farmacológico , Células A549 , Aldeídos/síntese química , Aldeídos/química , Aldeídos/farmacologia , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cisplatino/química , Cisplatino/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Interações Hidrofóbicas e Hidrofílicas , MicroRNAs/genética , Estrutura Molecular , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Oxazocinas/síntese química , Oxazocinas/química , Oxazocinas/farmacologia , Pirimidinonas/síntese química , Pirimidinonas/química , Pirimidinonas/farmacologia , Relação Estrutura-AtividadeRESUMO
A new class of tricyclic heterocycles 4H-benzo[g][1,2,3]triazolo[5,1-c][1,4]oxazocines was synthesized through a Knoevenagel condensation/azide-alkyne cycloaddition reaction cascade in one-pot operation. These eight membered ring containing heterocycles exhibited moderately high anticancer activity against four cancer cell lines; human cervix cancer cell line (HeLa), human prostate cancer cell line (DU145), human breast cancer cell line (MCF-7) and human breast adenocarcinoma epithelial cell line (MDA-MB-231). Our results indicate that these compounds have a weak cytotoxic effect on normal human mammary epithelial cell line (MCF-10A). Cell cycle and apoptosis assay indicate that they inhibit the cell cycle at the G2/M phase and induce apoptosis. Through the RED100 assay, it is evident that they have potential to inhibit pBR 322 plasmid DNA cleavage by BamH1. UV-visible, fluorescence titration and viscosity studies suggested that these compounds possess DNA binding affinity.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , DNA/metabolismo , Oxazocinas/química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Células HeLa , Humanos , Células MCF-7 , Oxazocinas/farmacologia , Espectrofotometria Ultravioleta , Relação Estrutura-Atividade , ViscosidadeRESUMO
Several benzoxazocenones have been found to exhibit novel cellular activities. In the present study, we report a gold(I)-catalyzed 8-endo-dig hydroalkoxylation reaction of alkynamides to access analogous oxazocenone scaffolds. This methodology provided an advanced intermediate, which was elaborated to a des-benzo analog of a bioactive benzoxazocenone.
Assuntos
Alcinos/química , Amidas/química , Ouro/química , Oxazocinas/síntese química , Aldeídos , Catálise , Ciclização , Estrutura Molecular , Oxazocinas/química , EstereoisomerismoRESUMO
Five series of heterocycles with extraordinary structural diversity have been regiospecifically synthesized from the same Morita-Baylis-Hillman Acetates (MBHAs). All four potential electrophilic sites (α, ß, γ, δ) of MBHAs are proved to be reactive.
Assuntos
Acetatos/química , Compostos Heterocíclicos/química , Indolizinas/síntese química , Indolizinas/química , Oxazocinas/síntese química , Oxazocinas/química , Pirazóis/síntese química , Pirazóis/química , Piridinas/síntese química , Piridinas/química , Pirróis/síntese química , Pirróis/químicaRESUMO
Facile synthesis of two new series of tetracyclic azepine and oxazocine analogs is described. These analogs were evaluated for their potential as MAPKAP-K2 (MK2) inhibitors and several were found to be potent at inhibiting MK2 with a non-ATP competitive binding mode.
Assuntos
Azepinas/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Oxazocinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Azepinas/síntese química , Azepinas/química , Humanos , Estrutura Molecular , Oxazocinas/síntese química , Oxazocinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A short and high yield synthetic route to dibenz[b,f][1,5]oxazocines has been developed using Pd catalyzed intramolecular cycloamination reaction. Receptor binding assay using [125I]-dynorphin demonstrated that one of the derivative, 5b showed selective κ-opioidergic property.
Assuntos
Antineoplásicos/farmacologia , Oxazocinas/farmacologia , Receptores Opioides kappa/agonistas , Aminação , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação/efeitos dos fármacos , Catálise , Proliferação de Células/efeitos dos fármacos , Glioma/enzimologia , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Oxazocinas/síntese química , Oxazocinas/química , Paládio/química , Estereoisomerismo , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A diverse group of novel medium ring heterocycles derived from naturally abundant proteinogenic amino acids were evaluated for their potency towards antithrombotic activity. The more potent benzofused oxazepine and oxazocine scaffolds were diversified by incorporating different amino acids at the position number 3. Further the effect of ring size has also been taken into account and it was observed that the eight-membered oxazocines ane more potent compared to the corresponding oxazepines.
Assuntos
Aminoácidos/química , Fibrinolíticos/química , Compostos Heterocíclicos com 2 Anéis/química , Benzodiazepinas/química , Fibrinolíticos/síntese química , Fibrinolíticos/farmacologia , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/farmacologia , Oxazepinas/química , Oxazocinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
This study aimed to identify the crucial structural features of 2-substituted 8-methylpyrimido[4,5-b][1,5]oxazocine derivatives. Axially chiral 8-methylpyrimido[4,5-b][1,5]oxazocines bearing a substituent at the C-2 position were synthesized and evaluated as NK(1) antagonists. The results revealed that (aR, 8S)-stereochemistry and the substituent at the C-2 position are important for NK(1) receptor recognition.
Assuntos
Antagonistas dos Receptores de Neurocinina-1 , Oxazocinas/química , Oxazocinas/farmacologia , Animais , Relação Dose-Resposta a Droga , Cobaias , Íleo/efeitos dos fármacos , Estrutura Molecular , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A series of novel bicyclic pyrimidine derivatives was prepared as part of a search for NK1 antagonist aimed at the treatment of urinary incontinence. Among them, 3g, a pyrimido[4,5-b][1,5]oxazocine derivative, bearing a 4-acetylpiperazinyl group and a 2-methylphenyl group, was shown to have potent NK1 antagonist activity with a K(B) value of 0.105 nM and markedly increased the effective bladder capacity of guinea pigs (59.4% at 0.3 mg/kg iv and 62.8% at 3 mg/kg id). Furthermore, the effect of 3g on bladder function appeared to differ from that of tolterodine, another classical anti-pollakiuria agent, as determined by the distention-induced rhythmic bladder contraction assay using a urethane-anesthetized guinea pig model. Compound 3g is expected to be a promising agent for the treatment of urinary incontinence.
Assuntos
Antagonistas dos Receptores de Neurocinina-1 , Oxazocinas/síntese química , Oxazocinas/farmacologia , Animais , Avaliação Pré-Clínica de Medicamentos , Cobaias , Espectroscopia de Ressonância Magnética , Contração Muscular/efeitos dos fármacos , Oxazocinas/química , Espectrometria de Massas por Ionização por Electrospray , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiologiaRESUMO
Novel 9-substituted-7-aryl-3,4,5,6-tetrahydro-2H-pyrido[4,3-b]- and [2,3-b]-1,5-oxazocin-6-ones were designed and prepared as part of a search for NK1 antagonists. Structure-activity relationship studies indicated that the conformational restriction resulting from the incorporation of an oxazocine ring and the presence of a terminal heteroatom on the cyclic amino group at the C-9 position play important roles in NK1, receptor recognition.
Assuntos
Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/farmacologia , Antagonistas dos Receptores de Neurocinina-1 , Oxazocinas/síntese química , Oxazocinas/farmacologia , Animais , Desenho de Fármacos , Cobaias , Compostos Heterocíclicos com 2 Anéis/química , Íleo/efeitos dos fármacos , Íleo/metabolismo , Microssomos/efeitos dos fármacos , Microssomos/metabolismo , Estrutura Molecular , Oxazocinas/química , Ratos , Receptores da Neurocinina-1/metabolismo , Relação Estrutura-Atividade , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiologiaRESUMO
The structurally novel pyrimido[4,5-b][1,5]oxazocine derivative 3, a hybrid compound of pyrido[4,3-b]- and [2,3-b]-1,5-oxazocine (1 and 2, respectively), was designed and synthesized. We examined the atropisomeric property and the NK1 antagonist activity of 3. Compound 3 was found to possess both a feature of 1, free rotation about the biaryl bond, and a feature of 2, potent in vivo activity.
Assuntos
Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Antagonistas dos Receptores de Neurocinina-1 , Oxazocinas/síntese química , Oxazocinas/farmacologia , Animais , Avaliação Pré-Clínica de Medicamentos , Cobaias , Compostos Heterocíclicos/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Oxazocinas/química , Relação Estrutura-Atividade , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiologiaRESUMO
Previously we reported on the synthesis and properties of a series of highly potent piperidinyl 2-subsituted-3-cyano-1-naphthamide NK1 antagonists that includes 3 and 4. Here we report our efforts to alleviate a troublesome atropisomeric property of those derivatives by introduction of a tethering bridge that, in addition, could be used to lock the resulting cyclic derivatives in a purported NK1 pharmacophore conformation. Using 3 as a starting point, the naphtho[2,1-b][1,5]oxazocine, 17, was found to contain the optimal ring tether size (8) for retaining NK1 activity, was more NK1 versus NK2 selective, and reduced the number of atropisomers from four to two. Cyclic derivatives 29 and 32, which exist as essentially single atropisomers in the purported pharmacophore conformation, were prepared in the closely related naphtho[1,2-f][1,4]oxazocine series as part of an effort to use mono methyl substitution of the tethering bridge as a conformation stabilizing factor. Both 29 and 32 were found to be less active as NK1 antagonists than the non-methylated parent 28 possibly due to methyl group destabilization of receptor interaction. We discuss the above findings in the context of a previously proposed NK1 pharmacophore model and present a further refinement of that model.