Zinc binding groups for histone deacetylase inhibitors

Zhang, Lei; Zhang, Jian; Jiang, Qixiao; Zhang, Li; Song, Weiguo

doi:10.1080/14756366.2017.1417274

Cited by 187 publications

(138 citation statements)

References 71 publications

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“…[20] Incorporating a benzamide moiety as an alternative ZBG group, instead of hydroxamic acid, generally has yielded inhibition selectivity for class I HDACs. [21,22] For instance, chidamide selectively inhibits class I HDAC1-3 at low nanomolar concentrations. [23] In recent years, many new acridine analogues with antitumor activity have been reported as Topo inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Anticancer Research of N‐(2‐aminophenyl)benzamide Acridine Derivatives as Dual Topoisomerase I and Isoform‐Selective HDAC Inhibitors

Zhang

Liu

et al. 2020

ChemistrySelect

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Topoisomerase (Topo) and histone deacetylase (HDAC) are considered to be effective targets for the treatment of cancer. In this study, 16 new N‐(2‐aminophenyl)benzamide acridine analogues (8 a‐8 p) were designed and synthesized as Topo I and subtype‐selective HDAC inhibitors. Most of the compounds displayed good antiproliferative activity against CCRF‐CEM, K562 and U937 cells. Among them, 8 a demonstrated the highest anti‐proliferative activity (IC50=0.12‐0.35 μM). Further studies showed that 8 a and some analogues displayed Topo I inhibitory activity and exhibited selective inhibition for HDAC1 (class I HDAC). Additionally, 8 a can significantly induce DNA damage and histone H3 acetylation in these tested cancer cells. Moreover, 8 a triggered dose‐dependent G0/G1 cell cycle arrest and induced cellular apoptosis. This study provides new perspectives for the further structural optimization of N‐(2‐aminophenyl)benzamide acridine analogues for use in cancer research.

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Section: Introductionmentioning

confidence: 99%

Synthesis and Anticancer Research of N‐(2‐aminophenyl)benzamide Acridine Derivatives as Dual Topoisomerase I and Isoform‐Selective HDAC Inhibitors

Zhang

Liu

et al. 2020

ChemistrySelect

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“…HDAC inhibitors are grouped structurally into four classes, hydroxamic acids, cyclic tetrapeptides, benzamides, and shortchain fatty acids 20,21 . Most classes of HDAC inhibitors contain the common pharmacophore, which is composed of three distinct domains, a zinc-binding domain, a linker domain, and a cap domain 37,38 . The zinc-binding domain chelates the catalytic Zn 2þ ion in the active site, which is critical for catalytic function of HDACs, the cap domain is a surface recognition group that interacts with the entrance of the active site pocket, and the linker domain connects the cap domain to the zinc-binding domain.…”

Section: Introductionmentioning

confidence: 99%

Hybrid inhibitors of DNA and HDACs remarkably enhance cytotoxicity in leukaemia cells

Song

Park

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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Chlorambucil is a nitrogen mustard-based DNA alkylating drug, which is widely used as a front-line treatment of chronic lymphocytic leukaemia (CLL). Despite its widespread application and success for the initial treatment of leukaemia, a majority of patients eventually develop acquired resistance to chlorambucil. In this regard, we have designed and synthesised a novel hybrid molecule, chloram-HDi that simultaneously impairs DNA and HDAC enzymes. Chloram-HDi efficiently inhibits the proliferation of HL-60 and U937 leukaemia cells with GI 50 values of 1.24 mM and 1.75 mM, whereas chlorambucil exhibits GI 50 values of 21.1 mM and 37.7 mM against HL-60 and U937 leukaemia cells, respectively. The mechanism behind its remarkably enhanced cytotoxicity is that chloram-HDi not only causes a significant DNA damage of leukaemia cells but also downregulates DNA repair protein, Rad52, resulting in the escalation of its DNAdamaging effect. Furthermore, chloram-HDi inhibits HDAC enzymes to induce the acetylation of a-tubulin and histone H3. ARTICLE HISTORY

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“…Many reports demonstrate that HDACs are overexpressed in several types of cancer [3,4]. Therefore, they represent a valuable target for cancer treatment [5].…”

Section: Introductionmentioning

confidence: 99%

“…Thiourea itself can coordinate metals through its sulfur or through one of its nitrogen atoms [18][19][20]. The most common disadvantages encountered with these classes of inhibitors are related to the poor pharmacokinetic profile and enzyme non-specificity of hydroxamates, in vivo toxicity of benzamides due to the free o-amine group, and the weak binding of the carboxylic acids to zinc ion [5]. These problems encouraged us to design new compounds that keep both the hydrophobic cap and linker but with a new, unique ZBG.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Docking Study of Acyl Thiourea Derivatives as Possible Histone Deacetylase Inhibitors with a Novel Zinc Binding Group

Al-Amily

Mohammed

2019

Sci. Pharm.

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Histone deacetylase inhibitors with zinc binding groups often exhibit drawbacks like non-selectivity or toxic effects. Thus, there are continuous efforts to modify the currently available inhibitors or to discover new derivatives to overcome these problems. One approach is to synthesize new compounds with novel zinc binding groups. The present study describes the utilization of acyl thiourea functionality, known to possess the ability to complex with metals, to be a novel zinc binding group incorporated into the designed histone deacetylase inhibitors. N-adipoyl monoanilide thiourea (4) and N-pimeloyl monoanilide thiourea (5) have been synthesized and characterized successfully. They showed inhibition of growth of human colon adenocarcinoma and mouse hepatoblastoma cells with low cytotoxic effect against normal human breast cells. Their binding mode to the active site of several histone deacetylases has been studied by docking and the results gave a preliminary indication that they could be successful histone deacetylase inhibitors.

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Zinc binding groups for histone deacetylase inhibitors

Cited by 187 publications

References 71 publications

Synthesis and Anticancer Research of N‐(2‐aminophenyl)benzamide Acridine Derivatives as Dual Topoisomerase I and Isoform‐Selective HDAC Inhibitors

Synthesis and Anticancer Research of N‐(2‐aminophenyl)benzamide Acridine Derivatives as Dual Topoisomerase I and Isoform‐Selective HDAC Inhibitors

Hybrid inhibitors of DNA and HDACs remarkably enhance cytotoxicity in leukaemia cells

Design, Synthesis, and Docking Study of Acyl Thiourea Derivatives as Possible Histone Deacetylase Inhibitors with a Novel Zinc Binding Group

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