RESUMO
A novel class of heat shock protein 90 (Hsp90) inhibitors was developed after a low throughput screen (LTS) of a focused library containing approximately 21K compounds selected by virtual screening. The initial [1-{3-H-imidazo[4-5-c]pyridin-2-yl}-3,4-dihydro-2H-pyrido[2,1-a]isoindole-6-one] (1) compound showed moderate activity (IC(50) = 7.6 µM on Hsp82, the yeast homologue of Hsp90). A high-resolution X-ray structure shows that compound 1 binds into an "induced" hydrophobic pocket, 10-15 Å away from the ATP/resorcinol binding site. Iterative cycles of structure-based drug design (SBDD) and chemical synthesis led to the design and preparation of analogues with improved affinity. These optimized molecules make productive interactions within the ATP binding site as reported by other Hsp90 inhibitors. This resulted in compound 8, which is a highly potent inhibitor in biochemical and cellular assays (K(d) = 0.35 nM on Hsp90; IC(50) = 30 nM on SKBr3 mammary carcinoma cells) and in an in vivo leukemia model.
Assuntos
Antineoplásicos/síntese química , Fluorenos/síntese química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Compostos Heterocíclicos com 3 Anéis/síntese química , Imidazóis/síntese química , Piridinas/síntese química , Trifosfato de Adenosina/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Fluorenos/química , Fluorenos/farmacologia , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Imidazóis/química , Imidazóis/farmacologia , Leucemia/tratamento farmacológico , Camundongos , Modelos Moleculares , Ligação Proteica , Piridinas/química , Piridinas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Original cyclosporin A (CsA) derivatives bearing various alkylthio side chains at the sarcosine residue 3 (R configuration) and for the most potent and selective compounds a 4'-hydroxyl group at the Me-Leucine residue 4 were prepared in one or two steps from commercially available CsA. The [2-(dimethyl or diethylamino)-ethylthio-Sar](3)-[(4'-OH)MeLeu](4)-CsA derivatives 3k and 3l displayed potent in vitro anti-HIV-1 (IC(50) approximately 46 nM) and low immunosuppressive activities (IC(50)>or=1500 nM).