Aroyl-pyrrolyl hydroxyamides: Influence of pyrrole C4-phenylacetyl substitution on histone deacetylase inhibition

The novel aroyl-pyrrolyl hydroxyamides 4a-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 HDAC's 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 4b) 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 4a-a') abated the slight (3-fold) selectivity interesting, dose-dependent antiproliferative and cytodifferentiation properties against human acute promyelocytic leukemia HL-60 cells.