RESUMO
Histone acetyltransferases (HATs) are enzymes able to acetylate lysine side chains of histones. They play essential roles in normal cell function as well as in pathogenesis of a broad set of diseases, including multiple cancers, HIV, diabetes mellitus, and neurodegenerative disorders. Moreover, several HATs are able to acetylate various non-histone protein substrates e.g. transcription factors, enzymes involved in glycolysis, fatty acid and glycogen metabolism, the tricarboxylic acid and urea cycles, suggesting that lysine acetylation represents an important regulatory mechanism similar to protein phosphorylation. Small molecule inhibitors of histone acetyltransferases have been developed in the last years and proved to be powerful tools to provide new insights into the mechanisms and the role of protein acetylation in gene regulation. This article highlights recent advances in the development of small molecule modulators of histone acetyltransferases.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Histona Acetiltransferases/antagonistas & inibidores , Histona Acetiltransferases/química , Histona Acetiltransferases/metabolismo , Acetilação/efeitos dos fármacos , Animais , Ciclo do Ácido Cítrico/efeitos dos fármacos , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/enzimologia , Inibidores Enzimáticos/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Glicogênio/metabolismo , Glicólise/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/enzimologia , Histonas/química , Histonas/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/enzimologia , Fatores de Transcrição/metabolismoRESUMO
Recently, the structure of BAY 58-2667 bound to the Nostoc sp. H-NOX domain was published. On the basis of this structural information, we designed BAY 58-2667 derivatives and tested their effects on soluble guanylyl cyclase (sGC) activity. Derivative 20 activated sGC 4.8-fold more than BAY 58-2667. Co-crystallization of 20 with the Ns H-NOX domain revealed that the increased conformational distortion at the C-terminal region of αF helix containing 110-114 residues contributes to the higher activation triggered by 20.
Assuntos
Benzoatos/farmacologia , Guanilato Ciclase/metabolismo , Heme/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Benzoatos/síntese química , Benzoatos/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ativação Enzimática , Heme/química , Modelos Moleculares , Conformação Molecular/efeitos dos fármacos , Óxido Nítrico/metabolismo , Nostoc/enzimologia , Receptores Citoplasmáticos e Nucleares/agonistas , Guanilil Ciclase Solúvel , Relação Estrutura-AtividadeRESUMO
A carbopalladation cascade reaction of easily accessible gem-dibromoolefins and alkynes furnishes monobenzo- and mononaphthopentalenes. The new chromophores accessed by this short route exhibit small HOMO-LUMO gaps and redox amphoteric behavior with tunable redox potentials.
RESUMO
The application of the Nazarov photocyclization as a mild and efficient method for access to the basic core of novel indoloditerpenoid derivatives is reported. The detailed synthesis of these new analogues of terpendole E, as well as their evaluation as potential inhibitors of KSP, is described.