Indole-derived psammaplin a analogues as epigenetic modulators with multiple inhibitory activities

Raquel Pereira, Rosaria Benedetti, Santiago Pérez-Rodríguez, Angela Nebbioso, José García-Rodríguez, Vincenzo Carafa, Mayra Stuhldreier, Mariarosaria Conte, Fátima Rodríguez-Barrios, Hendrik G. Stunnenberg, Hinrich Gronemeyer, Lucia Altucci, Ángel R. De Lera

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

49 Citaten (Scopus)


A SAR study has been carried out around a modified scaffold of the natural product psammaplin A obtained by replacing the o-bromophenol unit by an indole ring. A series of indole psammaplin A constructs were generated in a short synthetic sequence that starts with the functionalization of the C3 indole position with in situ generated nitrosoacrylate, and this is followed by protection of the β-indole-α-oximinoesters, saponification, condensation with symmetrical diamines, and deprotection. Biochemical and cellular characterization using U937 and MCF-7 cells confirmed that many of these analogues displayed more potent actitivies than the parent natural product. Moreover, in addition to the 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 profiles. Because of their multi(epi)target features and their action in ex vivo samples, the indole-based psammaplin A derivatives are attractive molecules for the modulation of epigenetic disorders.

Originele taal-2Engels
Pagina's (van-tot)9467-9491
Aantal pagina's25
TijdschriftJournal of Medicinal Chemistry
Nummer van het tijdschrift22
StatusGepubliceerd - 26 nov. 2012
Extern gepubliceerdJa


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