RESUMO
This paper describes the implementation of a biochemical and biophysical screening strategy to identify and optimize small molecule Akt1 inhibitors that act through a mechanism distinct from that observed for kinase domain ATP-competitive inhibitors. With the aid of an unphosphorylated Akt1 cocrystal structure of 12j solved at 2.25 Å, it was possible to confirm that as a consequence of binding these novel inhibitors, the ATP binding cleft contained a number of hydrophobic residues that occlude ATP binding as expected. These Akt inhibitors potently inhibit intracellular Akt activation and its downstream target (PRAS40) in vitro. In vivo pharmacodynamic and pharmacokinetic studies with two examples, 12e and 12j, showed the series to be similarly effective at inhibiting the activation of Akt and an additional downstream effector (p70S6) following oral dosing in mice.
Assuntos
Trifosfato de Adenosina/fisiologia , Antineoplásicos/síntese química , Imidazóis/síntese química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Piridinas/síntese química , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Disponibilidade Biológica , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Imidazóis/química , Imidazóis/farmacologia , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Fosforilação , Ligação Proteica , Conformação Proteica , Piridinas/química , Piridinas/farmacologia , Proteínas Quinases S6 Ribossômicas 70-kDa/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
[reaction: see text] We have synthesized simple model systems to explore the possibility of photo-cross-linking between the pyrimidine bases and the side chains of the aromatic amino acids. Thymine/phenylalanine and thymine/tyrosine models gave cross-links, and thymine/tryptophan models gave complex mixtures; the cytosine/phenylalanine model was unreactive. The quantum yields for the model cross-linking reactions were 18-46 times smaller than those for thymine dimer formation. Biphotonic excitation contributes little to the yield of these reactions.
Assuntos
Aminoácidos Aromáticos/química , Reagentes de Ligações Cruzadas/química , DNA/química , Modelos Biológicos , Proteínas/química , Pirimidinas/químicaRESUMO
In this paper, we describe the synthesis of N-(6-cyano-1,3-dimethyl-2,4-dioxo-5-substituted-1,3-dihydropyridino[2,3-d] pyrimidin-7-yl)imides 1. We will show the synthesis of 1 using both conventional heating and microwave techniques. In addition, the imide was attached to polystyrene and this immobilized imide was equally as effective at acylating various primary and secondary amines as its solution-phase counterpart.