RESUMO
Specific inhibitors of protein phosphatase 2A (PP2A) mediate anticancer effects by augmenting the tumor-killing activity of natural killer (NK) cells. In this study, new PP2A inhibitors, aminocytostatins A-E, were isolated from Kitasatospora sp. MJ654-NF4 and structurally characterized. Aminocytostatins are derivatives of cytostatin, which is a specific PP2A inhibitor isolated from the same organism, and aminocytostatins have a characteristic amino group within the lactone moiety. Compared to cytostatin, aminocytostatin A showed a stronger inhibitory activity against PP2A in vitro and augmented the tumor-killing activity of NK cells in vivo. Furthermore, a docking model was generated to demonstrate the favorable activities of aminocytostatin A.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Organofosfatos/química , Organofosfatos/farmacologia , Proteína Fosfatase 2/antagonistas & inibidores , Pironas/química , Pironas/farmacologia , Streptomycetaceae/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Descoberta de Drogas , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
The histone acetyltransferase (HAT) activity of p300 is essential for androgen receptor (AR) function. Androgen-independent prostate cancer cells require AR-mediated transcriptional activation for their growth. These observations indicate that p300 HAT is a promising target to overcome such hormone-resistant cancer cells. We sought p300 HAT inhibitors among microbial metabolites. By culturing a production strain belonging to Penicillium, we identified two new compounds, NK13650A and NK13650B, which were obtained as specific p300 HAT inhibitors. Structural analyses of these compounds elucidated that NK13650s have novel chemical structures comprising several amino acids and citrate. We applied a newly developed biosynthesis-based method to reveal the absolute configuration at the citrate quaternary carbon. This was accomplished by feeding a (13)C-labeled biosynthetic precursor of citrate. NK13650s selectively inhibited the activity of p300 HAT but not that of Tip60 HAT. NK13650s showed inhibitory activity against agonist-induced AR transcriptional activation, and NK13650A treatment inhibited hormone-dependent and -independent growth of prostate cancer cells.
Assuntos
Antineoplásicos/farmacologia , Citratos/farmacologia , Dicetopiperazinas/farmacologia , Inibidores Enzimáticos/farmacologia , Histona Acetiltransferases/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citratos/química , Citratos/isolamento & purificação , Dicetopiperazinas/química , Dicetopiperazinas/isolamento & purificação , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Células HEK293 , Histona Acetiltransferases/metabolismo , Humanos , Conformação Molecular , Penicillium/química , Penicillium/metabolismo , Relação Estrutura-AtividadeRESUMO
Halstoctacoanolides A and B are 28-membered polyketide macrolactones and were isolated from Streptomyces halstedii HC34. The biosynthetic gene cluster (hls cluster) of halstoctacosanolides was completely identified from the genome library of Streptomyces halstedii HC34. DNA sequence analysis of ca. 100 kb region revealed that there were seven type I polyketide synthases (PKSs) and two cytochrome P450 monooxygenases in this cluster. Involvement of the gene cluster in the halstoctacosanolide biosynthesis was demonstrated by the gene disruption of P450 monooxygenase genes. The mutants produced a new deoxygenated halstoctacosanolide derivative, halstoctacosanolide C, which confirmed that the hls gene cluster was essential for the biosynthesis of halstoctacosanolides.
