Structure−Activity Relationships on Phenylalanine-Containing Inhibitors of
Histone Deacetylase: In Vitro Enzyme Inhibition, Induction of Differentiation,
and Inhibition of Proliferation in Friend Leukemic Cells
posted on 2002-06-20, 00:00authored bySybille Wittich, Hans Scherf, Changping Xie, Gerald Brosch, Peter Loidl, Clarissa Gerhäuser, Manfred Jung
Inhibitors of histone deacetylases (HDACs) are a new class of anticancer agents that affect
gene regulation. We had previously reported the first simple synthetic HDAC inhibitors with
in vitro activity at submicromolar concentrations. Here, we present structure−activity data
on modifications of a phenylalanine-containing lead compound including amino acid amides
as well as variations of the amino acid part. The compounds were tested for inhibition of maize
HD-2, rat liver HDAC, and for the induction of terminal cell differentiation and inhibition of
proliferation in Friend leukemic cells. In the amide series, in vitro inhibition was potentiated
up to 15-fold, but the potential to induce cell differentiation decreased. Interestingly, an HDAC
class selectivity was indicated among some of these amides. In the amino acid methyl ester
series, a biphenylalanine derivative was identified as a good enzyme inhibitor, which blocks
proliferation in the submicromolar range and is also a potent inducer of terminal cell
differentiation.