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Aroyl‐Pyrrolyl Hydroxyamides: Influence of Pyrrole C4‐Phenylacetyl Substitution on Histone Deacetylase Inhibition
Author(s) -
Mai Antonello,
Massa Silvio,
Valente Sergio,
Simeoni Silvia,
Ragno Rino,
Bottoni Patrizia,
Scatena Roberto,
Brosch Gerald
Publication year - 2006
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200500015
Subject(s) - substitution (logic) , pyrrole , histone deacetylase , acetylation , chemistry , histone , stereochemistry , biochemistry , philosophy , organic chemistry , gene , linguistics
The novel aroyl‐pyrrolyl hydroxyamides 4 a – a′ are analogues of the lead compound 3‐(1‐methyl‐4‐phenylacetyl‐1H‐pyrrol‐2‐yl)‐N‐hydroxy‐2‐propenamide ( 2 ) and are active as HDAC inhibitors. The benzene ring of 2 was substituted with a wide range of electron‐donating and electron‐withdrawing groups, and the effect was evaluated on three HDACs from maize, namely HD2, HD1‐B (a class I HDAC), and HD1‐A (a class II HDAC). Inhibition studies show that the benzene 3′ and, to a lesser extent, 4′ positions of 2 were the most suitable for the introduction of substituents, with the 3′‐chloro (in 4 b ) and the 3′‐methyl (in 4 k ) derivatives being the most potent compounds, reaching the same activity as SAHA. Inhibition data for 4 b , k against mouse HDAC1 were consistent with those observed in the maize enzyme. The substituent insertion on the benzene ring of 2 (compounds 4 a – a′ ) abated the slight (3‐fold) selectivity for class II HDACs displayed by 2 . Compound 4 b showed interesting, dose‐dependent antiproliferative and cytodifferentiation properties against human acute promyelocytic leukemia HL‐60 cells.