RESUMO
The synthesis and biological activities of a series of sulfonylbenzoyl-nitrostyrene derivatives, a novel class of selective bisubstrate type inhibitors of the EGF-receptor tyrosine protein kinase, are described. The most potent derivatives inhibited the EGF-R tyrosine kinase, using angiotensin II as exogenous substrate, with IC50 values of less than or equal to 1 microM. No inhibition of the v-abl tyrosine kinase or the serine/threonine kinases PKC and PK-A was observed. In addition, active derivatives (compounds 5 and 12) effectively blocked the autophosphorylation of the EGF-R in vitro. Starting from the acids 5, 7, and 9, a series of esters, amides, and peptides was synthesized with the aim of increasing cellular penetration. Amides 14-18 showed potent antiproliferative effects using the EGF-dependent Balb/MK mouse epidermal keratinocyte cell line. Additionally, with the amide 14 inhibition of EGF-R autophosphorylation was demonstrated in the A431 cell line. CAMM studies using a computer-generated model for the transition state of the gamma-phosphoryl transfer from ATP to a tyrosine moiety and fitting experiments using the highly potent derivative 7 (IC50 value = 54 nM) support the hypothesis that the sulfonylbenzoyl group mimics a diphosphate moiety in the transition state. These results demonstrate that the rational design of tyrosine kinase inhibitors, using the inhibitory nitrostyrene moiety as a tyrosine mimic together with the sulfonylbenzoyl moiety as a diphosphate mimic, leads to highly potent and selective multisubstrate type inhibitors.
Assuntos
Benzoatos/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Estirenos/farmacologia , Sulfonas/farmacologia , Angiotensina II/metabolismo , Animais , Benzoatos/química , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Fenômenos Químicos , Química , Simulação por Computador , Cristalografia , Ativação Enzimática/efeitos dos fármacos , Fator de Crescimento Epidérmico/farmacologia , Receptores ErbB , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Camundongos , Modelos Moleculares , Estrutura Molecular , Nitrocompostos/química , Nitrocompostos/farmacologia , Fosforilação , Proteínas Tirosina Quinases/metabolismo , Estirenos/química , Sulfonas/químicaRESUMO
A number of semisynthetic bicyclomycin derivatives have been prepared by modifications at various sites of the molecule. The preparation, characterization and antimicrobial evaluation of the new compounds is described. In contrast to bicyclomycin itself, the new derivatives 48 and 58 are also active against Proteus species. Otherwise, the antibacterial potency of the bicyclomycin molecule was found to be very sensitive to structural changes.
