RESUMO
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
Natural products that act as highly specific, small-molecule protein-binding agents and as modulators of protein-protein interactions are highly complex and exhibit functional groups with three-dimensional and stereochemical diversity. The complex three-dimensional display of chiral functional groups appears to be crucial for exhibiting specificity in protein binding and in differentiating between closely related proteins. The development of methods that allow a high-throughput access to three-dimensional, skelatally complex, polycyclic compounds having few asymmetric diversity sites is essential and a highly challenging task. In the postgenomic chemical biology age, in which there is a great desire to understand protein-protein interactions and to dissect protein networking-based signaling pathways by small molecules, the need for developing "stereocontrolled, diversity-oriented synthesis" methods to generate natural product-like libraries is of utmost importance.
Assuntos
Ligação Proteica , Genômica , Modelos Moleculares , Conformação Molecular , Compostos Orgânicos/síntese química , Compostos Orgânicos/química , EstereoisomerismoRESUMO
In the age of high-throughput biology, novel genes and proteins are emerging quickly. The need for developing organic synthesis-derived methods that allow rapid access to polyfunctional, complex natural product-like compounds is growing constantly, largely because these small-molecule-based compounds serve as smart, powerful tools both in understanding the roles and functions of emerging biological targets and in validating their biological responses. Developing asymmetric synthesis-derived organic reactions on solid phase allows the synthesis of complex natural product-like compounds in a high-throughput manner. Solid phase organic synthesis is now commonly utilized in the library synthesis of rather simple compounds (i.e., compounds with no multiple stereogenic centers). With few exceptions, the synthesis of complex natural product-like derivatives is still in its infancy. Some recent efforts made in this area indicate opportunities yet to be explored.
Assuntos
Fatores Biológicos/química , Fatores Biológicos/síntese química , Compostos Policíclicos/química , Compostos Policíclicos/síntese química , Técnicas de Química Combinatória , Genômica , Mimetismo Molecular , Biblioteca de Peptídeos , Ligação Proteica , Proteoma , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
With the goal of library generation using a polycyclic derivative 5 having an enamide functional group, a simple and practical, enantioselective synthesis of tetrahydroquinoline derivative 2 was achieved. The phenolic hydroxyl group in compound 2 was utilized as an anchoring site for solid-phase synthesis. The ring closing metathesis approach yielded the desired polycyclic product 5 on solid phase in five steps (overall 40% yield). Compound 5 is a novel scaffold for the library generation of natural product-like polycyclics having a functionalized medium ring for obtaining a new class of small molecules to be utilized as chemical probes.
RESUMO
A diversity-oriented solution and solid-phase synthesis of tetrahydroquinoline-based tricyclic derivatives has been achieved from enantiomerically pure, natural product-like bicyclic scaffold. The solution synthesis of enantiopure bicyclic scaffold was developed by asymmetric hetero Michael reaction. Our approach for the synthesis of polycyclic derivatives utilized regio- and stereoselective hetero Michael reaction and ring-closing metathesis as key steps in solution and on solid phase.