RESUMO
The mycobacterial cell wall frequently has been used as a target for drug development, and d-glutamate, synthesized by glutamate racemase (MurI), is an important component of peptidoglycan. While the essentiality of the murI gene has been shown in several bacterial species, including Escherichia coli, Bacillus anthracis, and Streptococcus pneumoniae, studies in mycobacteria have not yet provided definitive results. This study aimed to determine whether murI is indeed essential and can serve as a possible target for structure-aided drug design. We have achieved this goal by creating a ΔmurI strain of Mycobacterium smegmatis, a close relative of Mycobacterium tuberculosis. The deletion of the murI gene in M. smegmatis could be achieved only in minimal medium supplemented with D-glutamate, demonstrating that MurI is essential for growth and that glutamate racemase is the only source of D-glutamate for peptidoglycan synthesis in M. smegmatis.
Assuntos
Isomerases de Aminoácido/genética , Isomerases de Aminoácido/metabolismo , Genes Essenciais , Mycobacterium smegmatis/enzimologia , Mycobacterium smegmatis/crescimento & desenvolvimento , Parede Celular/metabolismo , Meios de Cultura/química , Deleção de Genes , Ácido Glutâmico/metabolismo , Mycobacterium smegmatis/genética , Peptidoglicano/metabolismoRESUMO
A series of arylphthalazine derivatives were synthesized and evaluated as antagonists of VEGF receptor II (VEGFR-2). IM-094482 57, which was prepared in two steps from commercially available starting materials, was found to be a potent inhibitor of VEGFR-2 in enzymatic, cellular and mitogenic assays (comparable activity to ZD-6474). Additionally, 57 inhibited the related receptor, VEGF receptor I (VEGFR-1), and showed excellent exposure when dosed orally to female CD-1 mice.
Assuntos
Ftalazinas/farmacocinética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Feminino , Isoquinolinas/síntese química , Isoquinolinas/farmacocinética , Camundongos , Camundongos Endogâmicos , Ftalazinas/administração & dosagem , Ftalazinas/síntese química , Piperidinas , Quinazolinas , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
Alanine racemase, encoded by the gene alr, is an important enzyme in the synthesis of d-alanine for peptidoglycan biosynthesis. Strains of Mycobacterium smegmatis with a deletion mutation of the alr gene were found to require d-alanine for growth in both rich and minimal media. This indicates that alanine racemase is the only source of d-alanine for cell wall biosynthesis in M. smegmatis and confirms alanine racemase as a viable target gene for antimycobacterial drug development.
Assuntos
Alanina Racemase/metabolismo , Alanina/deficiência , Mycobacterium smegmatis/enzimologia , Mycobacterium smegmatis/crescimento & desenvolvimento , Alanina/metabolismo , Alanina Racemase/genética , Antibacterianos/farmacologia , Farmacorresistência Bacteriana/genética , Deleção de Genes , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium smegmatis/genética , Fatores de TempoRESUMO
A novel class of 1-(isoquinolin-5-yl)-4-arylamino-phthalazines is described as inhibitors of vascular endothelial growth factor receptor II (VEGFR-2). Many compounds display VEGFR-2 inhibitory activity with an IC(50) as low as 0.017 microM in an HTRF enzymatic assay. The compounds also inhibit VEGFR-1, a related tyrosine kinase.
Assuntos
Isoquinolinas/farmacologia , Ftalazinas/farmacologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fluorimunoensaio , Humanos , Concentração Inibidora 50 , Isoquinolinas/síntese química , Ftalazinas/síntese química , Relação Estrutura-AtividadeRESUMO
A novel class of pyrimido[4,5-b]-1,4-benzoxazepines is described as inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase. Two compounds display potent EGFR inhibitory activity of less than 1 microM in cellular phosphorylation assays (IC(50) 0.47-0.69 microM) and are highly selective against a small kinase panel. Such compounds demonstrate anti-EGFR activity within a class that is different from any known EGFR inhibitor scaffolds. They also provide a basis for the design of kinase inhibitors with the desired selectivity profile.
Assuntos
Azepinas/síntese química , Azepinas/farmacologia , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Trifosfato de Adenosina/metabolismo , Azepinas/química , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Humanos , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Receptor ErbB-2/antagonistas & inibidores , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
A novel class of 4-arylamino-phthalazin-1-yl-benzamides is described as inhibitors of vascular endothelial growth factor receptor II (VEGFR-2). Several compounds display potent VEGFR-2 inhibitory activity with an IC50 as low as 0.078 microM in an HTRF enzymatic assay. These compounds are relatively selective against a small kinase panel.
Assuntos
Inibidores da Angiogênese/síntese química , Ftalazinas/síntese química , Inibidores de Proteínas Quinases/síntese química , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/farmacologia , Concentração Inibidora 50 , Ftalazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
Pyrimido-oxazepine based sub-micromolar inhibitors (2-4) for Aurora and FLT-3 were designed and synthesized. These preliminary results supported the potential use of pyrimido-oxazepines as a versatile template for developing specific kinase inhibitors.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Oxazepinas/farmacologia , Fosfotransferases/antagonistas & inibidores , Pirimidinas/farmacologia , Aurora Quinases , Humanos , Cinética , Modelos Moleculares , Oxazepinas/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/síntese química , Relação Estrutura-Atividade , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidoresRESUMO
A novel triazole-containing chemical series was shown to inhibit tubulin polymerization and cause cell cycle arrest in A431 cancer cells with EC(50) values in the single digit nanomolar range. Binding experiments demonstrated that representative active compounds of this class compete with colchicine for its binding site on tubulin. The syntheses and structure-activity relationship studies for the triazole derivatives are described herein.