Second-generation derivatives of the eukaryotic translation initiation inhibitor pateamine A targeting eIF4A as potential anticancer agents.
Bioorg Med Chem
; 22(1): 116-25, 2014 Jan 01.
Article
em En
| MEDLINE
| ID: mdl-24359706
ABSTRACT
A series of pateamine A (1) derivatives were synthesized for structure/activity relationship (SAR) studies and a selection of previous generation analogs were re-evaluated based on current information regarding the mechanism of action of these translation inhibitors. Structural modifications in the new generation of derivatives focused on alterations to the C19-C22 Z,E-diene and the trienyl side chain of the previously described simplified, des-methyl, des-amino pateamine A (DMDAPatA, 2). Derivatives were tested for anti-proliferative activity in cell culture and for inhibition of mammalian cap-dependent translation in vitro. Activity was highly dependent on the rigidity and conformation of the macrolide and the functionality of the side chain. The only well tolerated substitutions were replacement of the N,N-dimethyl amino group found on the side chain of 2 with other tertiary amine groups. SAR reported here suggests that this site may be modified in future studies to improve serum stability, cell-type specificity, and/or specificity towards rapidly proliferating cells.
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Base de dados:
MEDLINE
Assunto principal:
Tiazóis
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Macrolídeos
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Fatores de Iniciação em Eucariotos
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Compostos de Epóxi
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Antineoplásicos
Limite:
Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article