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

Citations Over TimeTop 10% of 2002 papers

Abstract

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.

Related Papers

• → Lowering Brain Phenylalanine Levels by Giving Other Large Neutral Amino Acids(1976)54 cited
• → The global gene expression response of Escherichia coli to l-phenylalanine(2004)53 cited
• → THE EFFECTS OF PHENYLALANINE ANALOGUES ON THE METABOLISM OF PHENYLALANINE IN RATS(1967)11 cited
• → Metabolism of D‐Phenylalanine and Its Effects on Concentrations of Brain Monoamines and Amino Acids in Rats–A Basic Study on Possibility of Clinical Use of D‐Phenylalanine as an Antidepressant–(1983)4 cited
• → FURTHER STUDIES ON THE DUAL REQUIREMENT FOR PHENYLALANINE AND TYROSINE IN TISSUE CULTURE(1961)5 cited