TY - JOUR
T1 - Indole-derived psammaplin a analogues as epigenetic modulators with multiple inhibitory activities
AU - Pereira, Raquel
AU - Benedetti, Rosaria
AU - Pérez-Rodríguez, Santiago
AU - Nebbioso, Angela
AU - García-Rodríguez, José
AU - Carafa, Vincenzo
AU - Stuhldreier, Mayra
AU - Conte, Mariarosaria
AU - Rodríguez-Barrios, Fátima
AU - Stunnenberg, Hendrik G.
AU - Gronemeyer, Hinrich
AU - Altucci, Lucia
AU - De Lera, Ángel R.
PY - 2012/11/26
Y1 - 2012/11/26
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84870021506&partnerID=8YFLogxK
U2 - 10.1021/jm300618u
DO - 10.1021/jm300618u
M3 - Article
C2 - 23030799
AN - SCOPUS:84870021506
SN - 0022-2623
VL - 55
SP - 9467
EP - 9491
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 22
ER -