Structure-based design of human immuno- and constitutive proteasomes inhibitors.
Eur J Med Chem
; 145: 570-587, 2018 Feb 10.
Article
em En
| MEDLINE
| ID: mdl-29339252
ABSTRACT
Starting from the X-ray structure of our previous tripeptidic linear mimics of TMC-95A in complex with yeast 20S proteasome, we introduced new structural features to induce a differential inhibition between human constitutive and immunoproteasome 20S particles. Libraries of 24 tripeptidic and 6 dipeptidic derivatives were synthesized. The optimized preparation of 3-hydroxyoxindolyl alanine residues from tryptophan and their incorporation in peptides were described. Several potent inhibitors of human constitutive proteasome and immunoproteasome acting at the nanomolar level (IC50â¯=â¯7.1â¯nM against the chymotrypsin-like activity for the best inhibitor) were obtained. A cytotoxic effect at the submicromolar level was observed against 6 human cancer cell lines.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Desenho de Fármacos
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Complexo de Endopeptidases do Proteassoma
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Inibidores de Proteassoma
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Antineoplásicos
Limite:
Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article