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

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.

Enhancement of growth and survival and alterations in Bcl-family proteins in β-thalassemic erythroid progenitors by novel short-chain fatty acid derivatives

“…While butyrates increase fetal globin expression in many patients [2,3,[29][30][31], hematological improvement does not consistently follow fetal globin induction in β-thalassemia, suggesting that the factors described above may be blunting the clinical response. Both chemotherapeutic agents and histone deacetylase inhibitors, such as butyrates, inhibit cell proliferation through induction of the cyclindependent kinase inhibitors p21 Cip and p27 Kip , with resulting cell cycle arrest, and are known to induce irreversible arrest or apoptosis in cancer cells [13][14][15][16]. Although normal cells can recover from this butyrate-induced growth arrest, β-thalassemia erythroid cells may be impaired in their ability to recover, due to the additional cellular stresses they endure.…”

“…This accelerated apoptosis may be aggravated by the cellular growth arrest induced by some of these fetal globin-inducing agents. For example, some histone deacetylase inhibitors, such as the butyrates, are known to inhibit cell proliferation, through arrest in the G 1 phase of the cell cycle, resulting in irreversible apoptosis in certain cell types [13][14][15][16]. We previously hypothesized that inhibition of cell proliferation by arginine butyrate and sodium phenylbutyrate may augment the accelerated erythroid apoptosis characteristic of β-thalassemia, and therefore sought to identify alternative HbF-inducing agents which were not growth-inhibitory.…”

Chemistry, Biology, and QSAR Studies of Substituted Biaryl Hydroxamates and Mercaptoacetamides as HDAC Inhibitors—Nanomolar‐Potency Inhibitors of Pancreatic Cancer Cell Growth

“…Reduction of the nitro group was achieved by Pd (OH) 2 catalyzed hydrogenation or in case of the tyrosine intermediate 3e, by using tin (II) chloride to avoid undesirable O-benzyl group cleavage. The resulting biphenylamines 4a-e were coupled with 7-benzyloxycarbamoylheptanoic acid (5) [24] by PyBOP to afford the corresponding amides 6a-e. Acid deprotection of the BOC group followed by hydrogenation led to the hydroxamates 7a-e.…”

Histone Deacetylase Inhibitors for Cancer Therapy

“…For example, acetylation of p53 results in stabilization of the protein and increased DNA binding and transactivation. [22][23][24][25][26][27][28] Inhibition of HDAC6 causes acetylation of HSP90 leading to proteosomal degradation of its client proteins such as the ErbB2 oncoprotein. [22][23][24] …”

“…The cap structure of HDACI interacts with amino acids at the entrance rim of the N-acetyl lysine binding channel of the HDAC, which determines the specificity of the inhibitor. 26 According to their chemical nature and mechanism of inhibition, HDACIs are classified into the following groups: short-chain fatty acids, epoxides, cyclic peptides, hydroxamic acids, benzamides, and other hybrid compounds. [3][4][5][6][7][8][9][27][28][29][37][38][39] In general, compared with inhibitors used in earlier studies, the newer agents are effective at nanomolar concentrations and are also less toxic.…”