RESUMO
The synthesis and use of an alkylsilyl-tethered large (500-600 microm) polystyrene resin (1) are disclosed. An optimized Suzuki coupling of bromine-functionalized polystyrene and a silicon-functionalized alkylborane generates the silicon-substituted polystyrene 1 in large scale (>100 g). Resin loading is accomplished by activation as the silyl triflate, which can accommodate even sterically encumbered secondary alcohols and phenols. Treatment with HF/pyridine for linker cleavage is mild, efficient, and amenable to an automated, large-scale distribution system. This platform delivers, minimally, 50 nmol of each small molecule derived from a diversity-oriented, split-pool synthesis on a per bead basis for use in both forward and reverse chemical genetic assays. This technology satisfies many requirements of a one bead-one stock solution approach to chemical genetics.
Assuntos
Sistemas de Liberação de Medicamentos , Poliestirenos/síntese química , Alcinos/química , Bromo/química , Sistemas de Liberação de Medicamentos/instrumentação , Sistemas de Liberação de Medicamentos/métodos , Desenho de Fármacos , Microesferas , Estrutura Molecular , Poliestirenos/química , Resinas Vegetais/química , Silanos/química , Relação Estrutura-AtividadeRESUMO
The cellular response to DNA damage is coordinated by the p53 protein. Mdm2, an oncoprotein, inhibits p53 and promotes p53 degradation. A recent high-resolution structure of the Mdm2-p53 complex may aid the design of small molecules to disrupt this interaction, for use in investigating the interaction further and for designing anticancer drugs.
