Aroyl-pyrrolyl hydroxyamides: influence of pyrrole C4-phenylacetyl substitution on histone deacetylase inhibition.
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.
Mai
Antonello
A
Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, Università degli Studi di Roma La Sapienza, P.le A. Moro 5, 00185 Roma, Italy. antonello.mai@uniroma1.it
Massa
Silvio
S
Valente
Sergio
S
Simeoni
Silvia
S
Ragno
Rino
R
Bottoni
Patrizia
P
Scatena
Roberto
R
Brosch
Gerald
G
D000577:Amides / Q000737:chemistry* / Q000494:pharmacology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D018922:HL-60 Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011758:Pyrroles / Q000737:chemistry; D013329:Structure-Activity Relationship
D000577:Amides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D011758:Pyrroles