Discovery of quinazolinyl-containing benzamides derivatives as novel HDAC1 inhibitors with in vitro and in vivo antitumor activities

Zixue, Zhang; Zhang, Qingwei; Zhang, Hao; Jiao, Min-Ru; Guo, Zheng; Peng, Xinyan; Fu, Lei; Li, Jianqi

doi:10.1016/j.bioorg.2021.105407

Cited by 9 publications

(9 citation statements)

References 26 publications

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“…These target compounds in this study were initially tested for inhibition of recombinant human HDAC1 since our work and that of others have clearly shown that HDAC1 is widely implicated in both transcriptional repression and chromatin remodeling. [22][23][24] First, we synthesized compounds 3a-3 g (►Table 1) and discussed the effect of different fragments in the cap region on the inhibitory activity of HDAC1. It was found that when the indole fragment was inserted, compound 3 g (HDAC1 IC 50 ¼ 0.803 µmol/L) had better enzyme inhibitory activity on HDAC1 than the positive control drug chidamide (HDAC1 IC 50 ¼ 1.280 µmol/L).…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…Inspired by our identification of a new HDACi for cancer treatment, 7 22 cap and ZBG were modified based on the structures of chidamide and entinostat (MS-275) ( Fig. 2 ), and a series of new benzamide HDAC1 inhibitors were designed and synthesized.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of Indole-Containing Benzamide Derivatives as HDAC1 Inhibitors with In Vitro and In Vivo Antitumor Activities

Peng

Zhang

et al. 2022

Pharmaceutical Fronts

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Targeting histone deacetylases (HDACs) has become an important focus in cancer inhibition. The pharmacophore of HDAC inhibitors (HDACis) reported so far is composed of three parts: a zinc-binding group (ZBG), a hydrophobic cavity-binding linker, and a surface-recognition cap interacting with HDAC surface located at the rim of active site cavity. This study aims to discover novel HDAC1 inhibitors with potent antitumor activities through modifying the cap and ZBG based on the structures of two marketed oral HDACis: chidamide and entinostat (MS-275). In this work, a series of benzamide derivatives were designed, synthesized, and evaluated for their antitumor activity. The structures of novel compounds were confirmed by 1H NMR (nuclear magnetic resonance) and ESI-MS (electrospray ionization mass spectrometry), and all target compounds were tested in both HDAC1 enzymatic inhibitory activity and cellular antiproliferative activity. Our data showed that the potent compound 3j exhibited good HDAC1 enzyme inhibitory activity and high antitumor cell proliferation activity against a selected set of cancer cells (PC-3, HCT-116, HUT-78, Jurkat E6–1, A549, Colo205, and MCF-7 cells) with no observed effects on human normal cells. In particular, compound 3j inhibited HDAC1 over the other tested HDAC isoforms (HDAC2, HDAC6, and HDAC8). Encouraged by this, the safety characteristics, molecular docking, preliminary pharmacokinetic characteristics, and antitumor effect in vivo of compound 3j were further investigated. Our data showed that compound 3j demonstrated acceptable safety profiles and favorable oral pharmacokinetic properties. Moreover, compound 3j could bind well with HDAC1 and showed significant antitumor activity in a PC-3 tumor xenograft model in vivo, though not as potent as positive control entinostat (MS-275). In summary, 3j might have therapeutic potential for the treatment of human cancers.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Discovery of Indole-Containing Benzamide Derivatives as HDAC1 Inhibitors with In Vitro and In Vivo Antitumor Activities

Peng

Zhang

et al. 2022

Pharmaceutical Fronts

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“…To further understand the interaction between 3c and HDAC1, molecular docking studies were performed to evaluate the possible binding modes of 3c with the active site of HDAC1 (PDB entry: 4BKX) using Syble/FlexX module. 13 The docking results showed that compound 3c could well insert into HDAC1 active sites (►Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

“…In vitro HDAC inhibition assays were performed as previously described. 13 In brief, 10 μL of enzyme solution (HeLa cell nuclear extract, HDAC1, HDAC2, HDAC6, or HDAC8, obtained from BPS Bioscience, San Diego, California, United States) was mixed with different concentrations of the tested compound (50 μL). The mixture was incubated at 37°C for 5 minutes, followed by adding 40 mL of the fluorogenic substrate.…”

Section: Fluorescence Assay Of Hdac Inhibition Activitiesmentioning

confidence: 99%

Design, Synthesis, and Evaluation of Benzoheterocyclic-Containing Derivatives as Novel HDAC1 Inhibitors

Jiao

Han

et al. 2022

Pharmaceutical Fronts

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In this study, the synthesis and biological evaluation of a variety of benzoheterocyclic-containing benzamide derivatives were described. Some of these compounds were proved to inhibiting the activity of histone deacetylase 1 (HDAC1) with IC50 values below the micromolar range, retarding proliferation of several human cancer cells, and surprisingly, not possessing toxicity to human normal cells and hERG K+ ion channels. Among those compounds, 3c was the most potent and efficacious derivative. Compound 3c was orally active and displayed excellent in vivo antitumor activity in a HCT-116 xenograft mice model.

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Heterocycles–Containing HDAC Inhibitors Active in Cancer: An Overview of the Last Fifteen Years

Raucci,

Castiello,

Mai

et al. 2024

ChemMedChem

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Cancer is one of the primary causes of mortality worldwide. Despite nowadays are numerous therapeutic treatments to fight tumor progression, it is still challenging to completely overcome it. It is known that Histone Deacetylases (HDACs), epigenetic enzymes that remove acetyl groups from lysines on histone’s tails, are overexpressed in various types of cancer, and their inhibition represents a valid therapeutic strategy. To date, some HDAC inhibitors have achieved FDA approval. Nevertheless, several other potential drug candidates have been developed. This review aims primarily to be comprehensive of the studies done so far regarding HDAC inhibitors bearing heterocyclic rings since their therapeutic potential is well known and has gained increasing interest in recent years. Hence, inserting heterocyclic moieties in the HDAC‐inhibiting scaffold can be a valuable strategy to provide potent and/or selective compounds. Here, in addition to summarizing the properties of novel heterocyclic HDAC inhibiting compounds, we also provide ideas for developing new, more potent, and selective compounds for treating cancer.

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Discovery of quinazolinyl-containing benzamides derivatives as novel HDAC1 inhibitors with in vitro and in vivo antitumor activities

Cited by 9 publications

References 26 publications

Discovery of Indole-Containing Benzamide Derivatives as HDAC1 Inhibitors with In Vitro and In Vivo Antitumor Activities

Discovery of Indole-Containing Benzamide Derivatives as HDAC1 Inhibitors with In Vitro and In Vivo Antitumor Activities

Design, Synthesis, and Evaluation of Benzoheterocyclic-Containing Derivatives as Novel HDAC1 Inhibitors

Heterocycles–Containing HDAC Inhibitors Active in Cancer: An Overview of the Last Fifteen Years

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