Aroyl-Pyrrolyl Hydroxyamides: influence of pyrrole C4-phenylacetyl substitution on histone deacetilase inhibition

The novel aroyl-pyrrolyl hydroxyamides 4a¿a¿ are analogues of the lead compound 3-(1-methyl-4-phenylacetyl-1H-pyrrol-2-yl)-Nhydroxy-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 4b) and the 3¿-methyl (in 4k) derivatives being the most potent compounds, reaching the same activity as SAHA. Inhibition data for 4b,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 for class II HDACs displayed by 2. Compound 4b showed interesting, dose-dependent antiproliferative and cytodifferentiation properties against human acute promyelocytic leukemia HL-60 cells.