RESUMO
A series of 3-O-acylated (-)-epigallocatechins were synthesized and their inhibition of steroid 5α-reductase was studied. They were prepared from the reaction of EGCG with tert-butyldimethylsilyl chloride followed by reductive cleavage of the ester bond. The resultant (-)-epigallocatechins penta-O-tert-butyldimethylsilyl ether was esterified with different fatty acids then desilylated to provide the corresponding products. The activity of 3-O-acylated (-)-epigallocatechins increased with the increasing carbon numbers of the fatty acid moiety, reaching maximum for 16 carbon atoms (compound 4h) with an IC50 of 0.53 µM, which was â¼12-fold more potent than EGCG (IC50=6.29 µM). Introduction of monounsaturated fatty acid provided the most potent compound 6 (IC50=0.48 µM), which showed moderate anti-tumor activity in vivo.
Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Inibidores de 5-alfa Redutase/farmacologia , Antineoplásicos/farmacologia , Catequina/análogos & derivados , Inibidores de 5-alfa Redutase/síntese química , Inibidores de 5-alfa Redutase/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Catequina/síntese química , Catequina/química , Catequina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos SCID , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A series of pyrrole-indolin-2-ones were synthesized, and their inhibition profile for Aurora kinases was studied. The potent compound 33 with phenylsulfonamido at the C-5 position and a carboxyethyl group at the C-3' position selectively inhibited Aurora A over Aurora B with IC50 values of 12 and 156 nM, respectively. Replacement of the carboxyl group with an amino group led to compound 47, which retained the activity for Aurora B and lost activity for Aurora A (IC50=2.19 microM). Computation modeling was used to address the different inhibition profiles of 33 and 47. Compounds 47 and 36 (the ethyl ester analogue of 33) inhibited the proliferation of HCT-116 and HT-29 cells and suppressed levels of the phosphorylated substrates of Aurora A and Aurora B in the Western blots.
Assuntos
Antineoplásicos/síntese química , Indóis/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirróis/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Aurora Quinase B , Aurora Quinases , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Células HT29 , Células HeLa , Histonas/metabolismo , Humanos , Indóis/química , Indóis/farmacologia , Modelos Moleculares , Fosforilação , Ligação Proteica , Pirróis/química , Pirróis/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The proteolytic processing of polyproteins by the 3CL protease of severe acute respiratory syndrome coronavirus is essential for the viral propagation. A series of tripeptide alpha,beta-unsaturated esters and ketomethylene isosteres, including AG7088, are synthesized and assayed to target the 3CL protease. Though AG7088 is inactive (IC50 > 100 microM), the ketomethylene isosteres and tripeptide alpha,beta-unsaturated esters containing both P1 and P2 phenylalanine residues show modest inhibitory activity (IC50 = 11-39 microM). The Phe-Phe dipeptide inhibitors 18a-e are designed on the basis of computer modeling of the enzyme-inhibitor complex. The most potent inhibitor 18c with an inhibition constant of 0.52 microM is obtained by condensation of the Phe-Phe dipeptide alpha,beta-unsaturated ester with 4-(dimethylamino)cinnamic acid. The cell-based assays also indicate that 18c is a nontoxic anti-SARS agent with an EC50 value of 0.18 microM.
Assuntos
Inibidores Enzimáticos/farmacologia , Isoxazóis/farmacologia , Mimetismo Molecular , Peptídeos/farmacologia , Pirrolidinonas/farmacologia , Proteínas Virais/antagonistas & inibidores , Animais , Western Blotting , Chlorocebus aethiops , Simulação por Computador , Proteases 3C de Coronavírus , Cisteína Endopeptidases , Endopeptidases/química , Inibidores Enzimáticos/química , Ésteres , Isoxazóis/química , Cinética , Espectroscopia de Ressonância Magnética , Espectrometria de Massas/métodos , Modelos Moleculares , Peptídeos/química , Fenilalanina/análogos & derivados , Pirrolidinonas/química , Valina/análogos & derivados , Células Vero , Proteínas Virais/químicaRESUMO
A diversified library of peptide anilides was prepared, and their inhibition activities against the SARS-CoV 3CL protease were examined by a fluorogenic tetradecapeptide substrate. The most potent inhibitor is an anilide derived from 2-chloro-4-nitroaniline, l-phenylalanine and 4-(dimethylamino)benzoic acid. This anilide is a competitive inhibitor of the SARS-CoV 3CL protease with K(i) = 0.03 muM. The molecular docking experiment indicates that the P1 residue of this anilide inhibitor is distant from the nucleophilic SH of Cys145 in the active site.