Design, synthesis, and preliminary bioactivity studies of substituted purine hydroxamic acid derivatives as novel histone deacetylase (HDAC) inhibitors

MedChemComm ◽  
2014 ◽  
Vol 5 (12) ◽  
pp. 1887-1891 ◽  
Author(s):  
Junhua Wang ◽  
Feng'e Sun ◽  
Leiqiang Han ◽  
Xuben Hou ◽  
Xiaole Pan ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Hydroxamic Acid ◽  
Tumor Therapy ◽  
Hdac Inhibitors ◽  
Hydroxamic Acids ◽  
Hdac Inhibition ◽  
Design Synthesis ◽  
Hydroxamic Acid Derivatives

Histone deacetylase (HDAC) is a clinically validated target for anti-tumor therapy. In order to increase HDAC inhibition and efficiency, we developed a series of novel substituted purine hydroxamic acids as potent HDAC inhibitors.

Design, synthesis, and evaluation of cyclic amide/imide-bearing hydroxamic acid derivatives as class-selective histone deacetylase (HDAC) inhibitors

2006 ◽  
Vol 14 (22) ◽  
pp. 7625-7651 ◽  
Author(s):  
Chihiro Shinji ◽  
Satoko Maeda ◽  
Keisuke Imai ◽  
Minoru Yoshida ◽  
Yuichi Hashimoto ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Hydroxamic Acid ◽  
Hdac Inhibitors ◽  
Design Synthesis ◽  
Cyclic Amide ◽  
Hydroxamic Acid Derivatives

Design, synthesis, and evaluation of isoindolinone-hydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors

2007 ◽  
Vol 17 (17) ◽  
pp. 4895-4900 ◽  
Author(s):  
Shoukou Lee ◽  
Chihiro Shinji ◽  
Kiyoshi Ogura ◽  
Motomu Shimizu ◽  
Satoko Maeda ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Hydroxamic Acid ◽  
Hdac Inhibitors ◽  
Design Synthesis ◽  
Hydroxamic Acid Derivatives

scholarly journals Hydroxamic Acid-Based Histone Deacetylase (HDAC) Inhibitors Can Mediate Neuroprotection Independent of HDAC Inhibition

2014 ◽  
Vol 34 (43) ◽  
pp. 14328-14337 ◽  
Author(s):  
S. F. Sleiman ◽  
D. E. Olson ◽  
M. W. Bourassa ◽  
S. S. Karuppagounder ◽  
Y.-L. Zhang ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Hydroxamic Acid ◽  
Hdac Inhibitors ◽  
Hdac Inhibition

Design, Synthesis and Biological Activity of New Hydroxamic Acids Containing 2-Imidazolylphenyl (oxy /thio )alkanoic Fragment

2020 ◽  
Vol 16 ◽  
Author(s):  
Desislava V. Stanisheva ◽  
Gjorgji Atanasov ◽  
Margarita D. Aposstolova ◽  
Ognyan I. Petrov
Keyword(s):  
Histone Deacetylase ◽  
Human Cancer ◽  
Hdac Inhibitors ◽  
Hydroxamic Acids ◽  
Substitution Pattern ◽  
Design Synthesis ◽  
Human Cancer Cell Lines ◽  
New Class ◽  
Chlorine Substitution ◽  
Therapeutic Compounds

Background: Histone deacetylase (HDAC) inhibitors are a new class of therapeutic compounds that show promising results in a series of preclinical and clinical anticancer studies. Hydroxamic acids belong to one of the most interesting classes of HDAC inhibitors. The member vorinostat (SAHA) was approved by the U.S. Food and Drug Administration for the treatment of cutaneous T-cell lymphoma. Methods: A series of eight novel hydroxamic acids containing 2-imidazolylphenyl(oxy/thio)alkanoic fragment designed to target histone deacetylase (HDAC) were synthesized in five steps from easily accessible 2(3H)-benzoxazolones and 2(3H)-benzthiazolones. The newly synthesized compounds were characterized by 1H, 13C NMR, and elemental analysis. Results: The structure-activity relationship was examined via linker length alternation and variation of the heteroatom (oxygen or sulfur) and chlorine substitution pattern of the starting materials. The compounds were tested for their cytotoxic activity against two human cancer cell lines (HT-29 and MDA-MB-231). Our data indicate that the compound 6.1d is active in the micromolar range with IC50 of 9.7 µM for MDA-MB-231 cells. DNA fragmentation analysis of the most active compounds confirmed that apoptosis could be one of the mechanisms involved in cell death. Conclusion: Taken together, the results revealed that 6d may become a promising lead compound for new anticancer drugs discovery.

Induction of Human γ Globin Gene Expression by Histone Deacetylase Inhibitors.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1583-1583
Author(s):  
Hua Cao
Keyword(s):  
Gene Expression ◽  
Histone Deacetylase ◽  
Hydroxamic Acid ◽  
Globin Gene ◽  
Hdac Inhibitors ◽  
Fetal Hemoglobin ◽  
Erythroid Progenitor ◽  
Globin Gene Expression ◽  
Hydroxamic Acid Derivatives

In previous studies we have showed that HDAC inhibitors including hydroxamic acid derivatives of short chain fatty acids butyryl hydroxamate, propionyl hydroxamate, subericbis hydroxamic acid (SBHA), and suberoylanilide hydroxamic acid (SAHA), are potent inducers of γ globin gene expression in in vitro luciferase assays and in cultures of human adult erythroid progenitor cells. In this present study, we used μLCR Aγ transgenic mice to test whether these compounds can also induce γ gene expression in vivo. We found that in addition to γ gene induction these compounds have considerable erythropoiesis activity. Thus, Propionyl and butyryl hydroxamate increased reticulocytes of mice by 71% and 139%, the in vivo BFUe counts by 75% and 51% and the in vivo γ gene expression by 33.9% and 71% respectively. SBHA and SAHA had no erythropoietic activity in vivo. We conclude that Hydroxamic acid derivatives can stimulate both the in vivo erythropoiesis and fetal globin production in a thalassemic murine model. Cyclic depsipeptide FK228 is a highly potent histone deacetylase inhibitor, currently in clinical trials in cancer patients. We investigated whether FK228 also functions as inducer of human γ globin gene expression and compared Hb F induction by FK228 to that of four other HDAC inhibitors, including hydroxamic acids (TSA), synthetic benzamides (MS-275), and two cyclic tetrapeptides, Apicidin and HC-Toxin. Our results showed that FK228 is the most potent fetal hemoglobin inducer among all the HDAC inhibitors tested in our laboratory. In a concentration of 0.84 nanomolar, FK228 induces γ gene promoter activity in the dual luciferase assay by 7.81 fold. In the human erythroid progenitor cell cultures it increases the levels of γ mRNA by 8.48 fold in a concentration of 0.143 nM. In contrast, fetal hemoglobin induction by other HDAC inhibitors is achieved in concentrations that are 100 to 1000 fold higher. We conclude that FK228 is a promising compound for induction of Hb F in patients with sickle cell disease and thalassemia.

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