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1.
J Nat Prod ; 79(5): 1267-75, 2016 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-27140429

RESUMO

Inhibition of the hypoxia-inducible factor 1α (HIF-1α) pathway by disrupting its association with the transcriptional coactivator p300 inhibits angiogenesis and tumor development. Development of HIF-1α/p300 inhibitors has been hampered by preclinical toxicity; therefore, we aimed to identify novel HIF-1α/p300 inhibitors. Using a cell-free assay designed to test compounds that block HIF-1α/p300 binding, 170 298 crude natural product extracts and prefractionated samples were screened, identifying 25 active extracts. One of these extracts, originating from the marine sponge Latrunculia sp., afforded six pyrroloiminoquinone alkaloids that were identified as positive hits (IC50 values: 1-35 µM). Luciferase assays confirmed inhibition of HIF-1α transcriptional activity by discorhabdin B (1) and its dimer (2), 3-dihydrodiscorhabdin C (3), makaluvamine F (5), discorhabdin H (8), discorhabdin L (9), and discorhabdin W (11) in HCT 116 colon cancer cells (0.1-10 µM, p < 0.05). Except for 11, all of these compounds also reduced HIF-1α transcriptional activity in LNCaP prostate cancer cells (0.1-10 µM, p < 0.05). These effects occurred at noncytotoxic concentrations (<50% cell death) under hypoxic conditions. At the downstream HIF-1α target level, compound 8 (0.5 µM) significantly decreased VEGF secretion in LNCaP cells (p < 0.05). In COLO 205 colon cancer cells no activity was shown in the luciferase or cytotoxicity assays. Pyrroloiminoquinone alkaloids are a novel class of HIF-1α inhibitors, which interrupt the protein-protein interaction between HIF-1α and p300 and consequently reduce HIF-related transcription.


Assuntos
Alcaloides/farmacologia , Proteína p300 Associada a E1A/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Poríferos/química , Pirroliminoquinonas/farmacologia , Alcaloides/química , Animais , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Compostos Heterocíclicos de 4 ou mais Anéis , Humanos , Masculino , Biologia Marinha , Estrutura Molecular , Neovascularização Patológica , Neoplasias da Próstata/tratamento farmacológico , Pirroliminoquinonas/química , Quinonas , Compostos de Espiro , Tiazepinas , Fator A de Crescimento do Endotélio Vascular/metabolismo
2.
J Am Chem Soc ; 137(16): 5569-75, 2015 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-25892103

RESUMO

Low oxygen environments are a hallmark of solid tumors, and transcription of many hypoxia-responsive genes needed for survival under these conditions is regulated by the transcription factor HIF-1 (hypoxia-inducible factor 1). Activation of HIF-1 requires binding of its α-subunit (HIF-1α) to the transcriptional coactivator protein p300. Inhibition of the p300/HIF-1α interaction can suppress HIF-1 activity. A screen for inhibitors of the protein binding domains of p300 (CH1) and HIF-1α (C-TAD) identified an extract of the marine ascidian Eudistoma sp. as active. Novel heterocyclic alkaloids eudistidines A (1) and B (2) were isolated from the extract, and their structures assigned by spectroscopic analyses. They contain an unprecedented tetracyclic core composed of two pyrimidine rings fused with an imidazole ring. Eudistidine A (1) was synthesized in a concise four-step sequence featuring a condensation/cyclization reaction cascade between 4-(2-aminophenyl)pyrimidin-2-amine (3) and 4-methoxy-phenylglyoxal (4), while eudistidine B (2) was synthesized in a similar fashion with glyoxylic acid (5) in place of 4. Naturally occurring eudistidine A (1) effectively inhibited CH1/C-TAD binding with an IC50 of 75 µM, and synthetic 1 had similar activity. The eudistidine A (1) scaffold, which can be synthesized in a concise, scalable manner, may provide potential therapeutic lead compounds or molecular probes to study p300/HIF-1α interactions and the role these proteins play in tumor response to low oxygen conditions. The unique structural scaffolds and functional group arrays often found in natural products make these secondary metabolites a rich source of new compounds that can disrupt critical protein-protein binding events.


Assuntos
Alcaloides/química , Alcaloides/farmacologia , Proteína p300 Associada a E1A/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Compostos Policíclicos/química , Compostos Policíclicos/farmacologia , Mapas de Interação de Proteínas/efeitos dos fármacos , Alcaloides/síntese química , Animais , Proteína p300 Associada a E1A/química , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/química , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Compostos Policíclicos/síntese química , Ligação Proteica/efeitos dos fármacos , Urocordados/química
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