Synthesis and biological evaluation of aminobenzamides containing purine moiety as class I histone deacetylases inhibitors

Mao, Pingting; He, Wei-Bao; Mai, Xi; Liu, Feng; Li, Na; Liao, Yijing; Zhu, Cai-Sheng; Li, Jian; Chen, Ting; Liu, Shu-Hao; Zhang, Qiming; He, Ling

doi:10.1016/j.bmc.2021.116599

Cited by 8 publications

(4 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mai et al addressed the rapid metabolism of hydroxamate-based HDAC inhibitors by developing 9-substituted purine-based aminobenzamide 43 (Figure ). This inhibitor has a 12-fold higher potency than entinostat, an IC 50 value of 55.1 nM for HDAC1, and improved metabolic stability compared to that of vorinostat. In HCT-116 cells, inhibitor 43 induced a dose-dependent increase in H3K9 and H4K5 acetylation levels, which persisted for up to 48 h. In contrast, vorinostat rapidly increased the H3K9 and H4K5 acetylation levels, which returned to the baseline in 12 h. This indicates that inhibitor 43 exhibits a slow-binding mechanism.…”

Section: Slow-binding Hdac Inhibitorsmentioning

confidence: 99%

Evolution of Slow-Binding Inhibitors Targeting Histone Deacetylase Isoforms

Mukherjee,

Zamani,

Suzuki

2023

J. Med. Chem.

View full text Add to dashboard Cite

Because the overexpression of histone deacetylase enzymes (HDACs) has been linked to numerous diseases, including various cancers and neurodegenerative disorders, HDAC inhibitors have emerged as promising therapeutic agents. However, most HDAC inhibitors lack both subclass and isoform selectivity, which leads to potential toxicity. Unlike classical hydroxamate HDAC inhibitors, slow-binding HDAC inhibitors form tight and prolonged bonds with HDAC enzymes. This distinct mechanism of action improves both selectivity and toxicity profiles, which makes slow-binding HDAC inhibitors a promising class of therapeutic agents for various diseases. Therefore, the development of slow-binding HDAC inhibitors that can effectively target a wide range of HDAC isoforms is crucial. This Perspective provides valuable insights into the potential and progress of slowbinding HDAC inhibitors as promising drug candidates for the treatment of various diseases. ■ SIGNIFICANCE • Drugs with longer residence times exhibit enhanced and sustained in vivo activity within animal models, potentially serving as an indicator of the drug's effectiveness. • This Perspective focuses on the recent development of slow-binding inhibitors designed to target specific HDAC isoforms through a critical understanding of the existing approaches. • It accentuates limitations and explores potential future directions within the field of HDAC inhibitor development, fostering a deeper comprehension of multifaceted issues through a scientifically driven narrative.

show abstract

Section: Slow-binding Hdac Inhibitorsmentioning

confidence: 99%

Evolution of Slow-Binding Inhibitors Targeting Histone Deacetylase Isoforms

Mukherjee,

Zamani,

Suzuki

2023

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

“…Mao et al [ 113 ] established novel series of 9-substituted purine aminobenzamides derivatives as class I HDACs. Compound 130 exhibited excellent activity in the HDAC isoform selectivity assay.…”

Section: Six-membered Heterocyclic Compoundsmentioning

confidence: 99%

An Overview of the Biological Evaluation of Selected Nitrogen-Containing Heterocycle Medicinal Chemistry Compounds

Ebenezer

Jordaan

Carena

et al. 2022

IJMS

View full text Add to dashboard Cite

Heterocyclic compounds are a class of compounds of natural origin with favorable properties and hence have major pharmaceutical significance. They have an exceptional adroitness favoring their use as diverse smart biomimetics, in addition to possessing an active pharmacophore in a complex structure. This has made them an indispensable motif in the drug discovery field. Heterocyclic compounds are usually classified according to the ring size, type, and the number of heteroatoms present in the ring. Among different heterocyclic ring systems, nitrogen heterocyclic compounds are more abundant in nature. They also have considerable pharmacological significance. This review highlights recent pioneering studies in the biological assessment of nitrogen-containing compounds, namely: triazoles, tetrazoles, imidazole/benzimidazoles, pyrimidines, and quinolines. It explores publications between April 2020 and February 2022 and will benefit researchers in medicinal chemistry and pharmacology. The present work is organized based on the size of the heterocyclic ring.

show abstract

“…Compound 7, a benzamide containing a purine moiety, inhibited HDAC1, HDAC3, and HDAC8, and compound 8, a benzamide with a quinazolinyl moiety, selectively inhibited HDAC1 over the other tested HDAC isoforms, whereas both compounds showed potent antiproliferative activities against different cancer cell lines. 21,22 Compound 9 is a potent HDAC1 and HDAC2 inhibitor with a phenol cap group, and compound 10 is a selective HDAC3 inhibitor that displayed antiproliferative activity at submicromolar concentrations against three cancer cell lines. 23,24 HDAC inhibitors have also been investigated as possible future treatments of other diseases.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Entinostat ( 5 , Figure ) also uses an N -(2-aminophenyl)-benzamide, inhibits mainly class I HDACs, and has been investigated in the clinic as a monotherapy and in combination with other drugs in solid tumors, leukemia, and lymphomas. , Finally, another N -(2-aminophenyl)-benzamide is mocetinostat ( 6 , Figure ), which selectively inhibits HDAC1, HDAC2, HDAC3, and HDAC11, with promising results against liver cancer, locally advanced or metastatic urothelial carcinoma, and Hodgkin’s lymphoma. , More recent examples of class I HDAC inhibitors include N -(2-aminophenyl)-benzamides 7 – 10 (Figure ), employing a wide range of different cap groups. Compound 7 , a benzamide containing a purine moiety, inhibited HDAC1, HDAC3, and HDAC8, and compound 8 , a benzamide with a quinazolinyl moiety, selectively inhibited HDAC1 over the other tested HDAC isoforms, whereas both compounds showed potent antiproliferative activities against different cancer cell lines. , Compound 9 is a potent HDAC1 and HDAC2 inhibitor with a phenol cap group, and compound 10 is a selective HDAC3 inhibitor that displayed antiproliferative activity at submicromolar concentrations against three cancer cell lines. , …”

Section: Introductionmentioning

confidence: 99%

N-(2-Aminophenyl)-benzamide Inhibitors of Class I HDAC Enzymes with Antiproliferative and Antifibrotic Activity

Gerokonstantis,

Mantzourani,

Gkikas

et al. 2023

J. Med. Chem.

View full text Add to dashboard Cite

Inhibitors of histone deacetylases (HDACs) have received special attention as novel anticancer agents. Among various types of synthetic inhibitors, benzamides constitute an important class, and one is an approved drug (chidamide). Here, we present a novel class of HDAC inhibitors containing the N-(2-aminophenyl)-benzamide functionality as the zinc-binding group linked to various cap groups, including the amino acids pyroglutamic acid and proline. We have identified benzamides that inhibit HADC1 and HDAC2 at nanomolar concentrations, with antiproliferative activity at micromolar concentrations against A549 and SF268 cancer cell lines. Docking studies shed light on the mode of binding of benzamide inhibitors to HDAC1, whereas cellular analysis revealed downregulated expression of EGFR mRNA and protein. Two benzamides were investigated in a mouse model of bleomycin-induced pulmonary fibrosis, and both showed efficacy on a preventative dosing schedule. N-(2-Aminophenyl)-benzamide inhibitors of class I HDACs might lead to new approaches for treating fibrotic disorders.

show abstract

Synthesis and biological evaluation of aminobenzamides containing purine moiety as class I histone deacetylases inhibitors

Cited by 8 publications

References 61 publications

Evolution of Slow-Binding Inhibitors Targeting Histone Deacetylase Isoforms

Evolution of Slow-Binding Inhibitors Targeting Histone Deacetylase Isoforms

An Overview of the Biological Evaluation of Selected Nitrogen-Containing Heterocycle Medicinal Chemistry Compounds

N-(2-Aminophenyl)-benzamide Inhibitors of Class I HDAC Enzymes with Antiproliferative and Antifibrotic Activity

Contact Info

Product

Resources

About