RESUMEN
Enzymatic inhibition of histone deacetylase (HDAC) activity is emerging as an innovative and effective approach for the treatment of cancer. A series of novel amide derivatives have been synthesized and evaluated for their ability to inhibit human HDACs. Multiple compounds were identified as potent HDAC inhibitors (HDACi), with IC(50) values in the low nanomolar (nM) range against enzyme activity in HeLa cell extracts and sub-microM for their in vitro anti-proliferative effect on cell lines. The introduction of an unsaturated linking group between the terminal aryl ring and the amide moiety was the key to obtain good potency. This approach yielded compounds such as (E)-N-[6-(hydroxyamino)-6-oxohexyl]-3-(7-quinolinyl)-2-propenamide (27) (HDAC IC(50) 8 nM) which showed potent in vivo activity in the P388 mouse leukemia syngeneic model (an increased lifespan (ILS) of 111% was obtained).
Asunto(s)
Amidas/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Amidas/química , Inhibidores Enzimáticos/química , Humanos , Espectroscopía de Resonancia Magnética , Relación Estructura-ActividadRESUMEN
A series of new N-hydroxyguanidines were synthesized and tested for electron acceptor activity on bovine milk xanthine oxidase using xanthine as reducing substrate. Manual inspection of the structure-activity data revealed that molecules containing nitro groups ("set A") show a different structure-activity relationship pattern compared to non-nitro compounds ("set B"). Accordingly separate QSAR models were built and validated for the two sets. Substantial differences were found in properties governing acceptor activity for the models, the only common property being sterical access to the imino nitrogen atom of the hydroxyguanidinimines. For set A molecules the presence of a nitro substituent at a certain distance range from the hydroxuguanidino group was most important. In addition, the presence of a nitro group in the ortho position interacting with NH(2) of the hydroxyguanidino group, and the mutual geometry of the phenyl ring, hydroxyguanidine, and imine groups was important for this set. By contrast, for set B molecules the acceptor activity was most influenced by the geometry of methoxy groups and the size and geometry of meta and para substituents of the phenyl ring.