Document Detail

Indole-derived Psammaplin A Analogs as Epigenetic Modulators With Multiple Inhibitory Activities.
MedLine Citation:
PMID:  23030799     Owner:  NLM     Status:  Publisher    
A SAR study has been carried out around the modified scaffold of the psammaplin A natural product obtained replacing the o-bromophenol unit by an indole ring. A series of indole-psammaplin A constructs were generated in a short synthetic sequence that attachs the oximinoamide chain to the corresponding C3 indole position. Biochemical and cellular characterization using U937 cells confirmed that many of these analogues displayed more potent actitivies than the parent natural product. Moreover, in addition to the already reported HDAC and DNMT dual epigenetic inhibitory profile of the parent compound, some analogues, notably 4a (UVI5008) also inhibited the NAD+-dependent SIRT deacetylase enzymes. The SAR study provides structural insights into the mechanism of action of these multiple epigenetic ligands and paves the way for additional structural exploration to optimize their pharmacological profile.
Raquel Pereira; Rosaria Benedetti; Santiago Perez-Rodriguez; Angela Nebbioso; José García-Rodríguez; Vincenzo Carafa; Mariarosaria Conte; Mayra C Stuhldreier; Fatima Rodriguez-Barrios; Hendrik Stunnenberg; Hinrich Gronemeyer; Lucia Altucci; Angel R de Lera
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-3
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  -     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-3     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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