RESUMO
We here introduce octahedral silicon serving as a structural center for the design of hydrolytically stable bioactive complexes as demonstrated with the generation of silicon-based high affinity DNA binders. This proof-of-principle study suggests that octahedral silicon complexes are falsely neglected, promising structural templates for widespread applications in chemical biology and medicinal chemistry.
Assuntos
DNA/química , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Compostos de Organossilício/química , Compostos de Organossilício/farmacologia , Dicroísmo Circular , Desenho de Fármacos , Modelos Moleculares , Conformação de Ácido Nucleico/efeitos dos fármacos , Desnaturação de Ácido Nucleico/efeitos dos fármacosRESUMO
Organometallic pyridocarbazole scaffolds are investigated as protein kinase inhibitors. Whereas our previous designs employed solely a maleimide pharmacophore for achieving the two crucial canonical hydrogen bonds to the hinge region of the ATP binding site, we have now extended our investigations to include the related lactam metallo-pyridocarbazoles. The synthetic access of the two regioisomeric lactam pyridocarbazoles is described, and the distinct biological properties of the two lactam scaffolds are revealed by employing a ruthenium half sandwich complex as a model system, resulting in organometallic lead structures for the inhibition of the protein kinases TrkA and CLK2. These new lactam metallo-pyridocarbazoles expand our existing molecular toolbox and assist toward the generation of metal complex scaffolds as lead structures for the design of selective inhibitors for numerous kinases of the human kinome.