RESUMO
Substituted 1,4-dihydropyridines were discovered as a novel and potent series of phosphodiesterase 4 (PDE4) inhibitors. Structure-activity relationships within this series have been carried out and studies revealed that the dihydropyridine core, with indole moiety and 3,4-dimethoxybenzyl group, is a potent analogue for PDE4 inhibition. These novel series of compounds were prepared via a 3-component reaction in a single pot. In vitro biological activity, modeling studies and crystallography data are also reported.
Assuntos
Di-Hidropiridinas/química , Di-Hidropiridinas/farmacologia , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacologia , Cristalografia por Raios X , Di-Hidropiridinas/síntese química , Descoberta de Drogas , Inibidores da Fosfodiesterase 4/síntese química , Relação Estrutura-AtividadeRESUMO
A new one-pot synthesis of 2-(hetero)aryl indoles via sequential C-C coupling followed by C-Si bond cleavage and a subsequent tandem C-C/C-N bond forming reaction is described. A variety of functionalized indole derivatives were prepared by conducting this four step reaction under Pd/C-Cu catalysis. The methodology involved coupling of (trimethylsilyl)acetylene with iodoarenes in the presence of 10% Pd/C-CuI-PPh(3) and triethylamine in MeOH, followed by treating the reaction mixture with K(2)CO(3) in aqueous MeOH, and finally coupling with o-iodoanilides. The single crystal X-ray data of a synthesized indole derivative is presented. Application of the methodology, in vitro pharmacological properties of the synthesized compound, along with a docking study is described.
Assuntos
Carbono/química , Cobre/química , Indóis/química , Indóis/síntese química , Paládio/química , Silício/química , Catálise , Ciclização , Ativação Enzimática/efeitos dos fármacos , Humanos , Indóis/farmacologia , Modelos Moleculares , Conformação Molecular , Sirtuína 1/metabolismoRESUMO
With the goal of identifying small molecule modulators of protein-protein interactions, we developed a solid-phase synthesis method, which was then successfully utilized in a library generation of 164 aminoindoline-derived, natural-product-like compounds. This library and several other related intermediates synthesized during this project were then subjected to different biological assays in search of small molecule modulators of focal adhesion kinase (FAK)-mediated signaling pathways. This study included (i) an in vitro, full length FAK inhibition assay, (ii) a cell proliferation assay, and (iii) a wound healing assay. In FAK inhibition assay, eight library members (5-12) and three aminoindoline derivatives (13, 14, and 2) were identified as promising candidates. Compounds 13 and 2 inhibited the FAK activity by 25-45% at 10 microM. These two lead compounds also showed activity in a wound healing assay. To our knowledge, these aminoindoline-derived small molecules belong to a new family of FAK inhibitors.
Assuntos
Técnicas de Química Combinatória/métodos , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Indóis/química , Indóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Proteína-Tirosina Quinases de Adesão Focal/química , Humanos , Modelos Moleculares , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Cicatrização/efeitos dos fármacosRESUMO
Inspired by bioactive indoline alkaloid natural products, here, we report a divergent synthesis approach that led to skeletally diverse indoline alkaloid-inspired compounds. The natural product-inspired compounds obtained were then subjected to a series of in vitro and cellular assays to examine their properties as modulators of focal adhesion kinase (FAK) activity. This study resulted in the identification of a promising lead inhibitor of FAK (42), which also showed activity in a wound healing and cell invasion assay. The in silico study of the lead compound (42) was also undertaken.
Assuntos
Inibidores Enzimáticos/farmacologia , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Alcaloides Indólicos/farmacologia , Indóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Humanos , Alcaloides Indólicos/síntese química , Alcaloides Indólicos/química , Indóis/síntese química , Indóis/química , Fosforilação/efeitos dos fármacos , Células Tumorais Cultivadas , Cicatrização/efeitos dos fármacosRESUMO
A general method has been developed for the synthesis of N-substituted oxindoles. The two-step process involves initial microwave-assisted amide bond formation between 2-halo-arylacetic acids and various alkylamines and anilines, followed by a palladium-catalyzed intramolecular amidation under aqueous conditions. In the case of alkylamines, the procedure can be carried out as a one-pot process without isolation of the intermediate amide. [structure: see text]
RESUMO
A general method for the synthesis of beta-aryl/alkylarylidene malonates is reported. The key step involves the coupling of an arylboronic acid to a beta-chloroalkyl/arylidene malonate, in the presence of K2CO3 and 1 mol % of the air-stable palladium catalyst (POPd) under microwave irradiation, to afford beta-aryl/alkylarylidene malonates in good yields. The combination of mild reaction conditions, air stable catalyst, microwave-enhanced chemistry, and high levels of functional group compatibility make this an attractive synthetic approach to this class of compounds.
