RESUMO
Mushrooms have been used for millennia as cancer remedies. Our goal was to screen several mushroom species from the rainforests of Costa Rica, looking for new antitumor molecules. Mushroom extracts were screened using two human cell lines: A549 (lung adenocarcinoma) and NL20 (immortalized normal lung epithelium). Extracts able to kill tumor cells while preserving non-tumor cells were considered "anticancer". The mushroom with better properties was Macrocybe titans. Positive extracts were fractionated further and tested for biological activity on the cell lines. The chemical structure of the active compound was partially elucidated through nuclear magnetic resonance, mass spectrometry, and other ancillary techniques. Chemical analysis showed that the active molecule was a triglyceride containing oleic acid, palmitic acid, and a more complex fatty acid with two double bonds. The synthesis of all possible triglycerides and biological testing identified the natural compound, which was named Macrocybin. A xenograft study showed that Macrocybin significantly reduces A549 tumor growth. In addition, Macrocybin treatment resulted in the upregulation of Caveolin-1 expression and the disassembly of the actin cytoskeleton in tumor cells (but not in normal cells). In conclusion, we have shown that Macrocybin constitutes a new biologically active compound that may be taken into consideration for cancer treatment.
Assuntos
Agaricales/química , Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologiaRESUMO
Herein we report investigations into the p38alpha MAP kinase activity of trisubstituted imidazoles that led to the identification of compounds possessing highly potent in vivo activity. The SAR of a novel series of imidazopyridines is demonstrated as well, resulting in compounds possessing cellular potency and enhanced in vivo activity in the rat collagen-induced arthritis model of chronic inflammation.
Assuntos
Anti-Inflamatórios/farmacologia , Imidazóis/farmacologia , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Piridinas/farmacologia , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/metabolismo , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacocinética , Benzimidazóis/química , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Edema/tratamento farmacológico , Receptores ErbB/metabolismo , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Fragmentos de Peptídeos/metabolismo , Piridinas/química , Piridinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismoRESUMO
We report the design and discovery of a 2-aminobenzimidazole-based series of potent and highly selective p38alphainhibitors. The lead compound 1 had low-nanomolar activity in both ATP competitive enzyme binding and inhibition of TNFalpha release in macrophages. Compound 18 showed excellent pharmacokinetics properties and oral activity in the rat collagen induced arthritis model compared with other p38 reference compounds. A SAR strategy to address CyP3A4 liability is also described.
Assuntos
Anti-Inflamatórios/síntese química , Benzimidazóis/síntese química , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Administração Oral , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Benzimidazóis/química , Benzimidazóis/farmacologia , Sítios de Ligação , Disponibilidade Biológica , Colágeno , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Lipopolissacarídeos/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Proteína Quinase 14 Ativada por Mitógeno/química , Modelos Moleculares , Ratos , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
The asymmetric synthesis and biological activity of (2S,1'S,2'R,3'R)-2-(2'-carboxy-3'-hydroxymethylcyclopropyl) glycine ((+)-3) is described. This novel C-3' substituted carboxy cyclopropyl glycine is a highly potent group 2 and group 3 mGluR agonist that has proven to be orally active in both fear potentiated startle (animal model for anxiety) and PCP-induced motor activation (animal model for psychosis) assays in rats.