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  • br Acknowledgments br Introduction Histone

    2022-06-23


    Acknowledgments
    Introduction Histone deacetylases (HDACs) related to tumor suppressor genes have become promising targets for the treatment of cancer [1,2]. Under the normal physiological conditions, Histone acetyltransferases (HATs) and histone deacetylases (HDACs) together regulate the acetylation status of histone in a dynamic equilibrium [3]. HDACs promote the removal of acetyl groups from the terminal lysine residues. Then the core histones tightly combine with DNA due to electrostatic interactions, preventing the access of protein complexes to the promoter binding site, and finally resulting in gene silencing. However, HATs cause the accumulation of acetylated histones, thereby leading to Nifuroxazide relaxation, and contributing to gene expression [[4], [5], [6]]. Excessive HDACs activity causes many genes to be unable to express normally, resulting in cell carcinoma [[7], [8], [9], [10], [11], [12], [13]]. In recent decades, HDACs have been widely proven to be promising targets for treating cancer caused by epigenetic abnormalities. HDAC inhibitors have been applied for clinical treatment for cutaneous cell lymphoma [14,15]. It has been illustrated that HDAC inhibitors exert anticancer activity through blocking cell cycle, promoting differentiation, inducing apoptosis and tumor immunity [11,16,17]. So far, 18 known HDAC isoforms have been divided into classes I, Ⅱ, Ⅲ, and IV according to their structure and function [18]. Class, I HDACs (HDAC 1, 2, 3 and 8), Class Ⅱ HDACs (HDAC 4, 5, 6, 7, 9 and 10) and Class IV Nifuroxazide (HDAC 11) are zinc-dependent HDACs, containing catalytic core domains with high homology [[19], [20], [21], [22]]. To date, many HDAC inhibitors (HDACIs) have been on the market or in clinical research stage, 4 of which have been approved by FDA: vorinostat (SAHA) [23] and romidepsin (FK228) [24] both for the treatment of cutaneous T-cell lymphoma, belinostat (PXD-101) [25] for the treatment of peripheral T-cell lymphoma, and panobinostat (LBH589) [26] for multiple myeloma. Chidamide (CS055) [27] approved by Chinese FDA was applied for the therapy of peripheral T-cell lymphoma. Several HDACIs have been in the clinical research stage such as tacedinaline (CI994) [28], entinostat (MS-275) [29] and mocetinostat (MGCD-0103) [30](Fig. 1). Generally, pharmacophore models of HDAC inhibitors consist of three structural parts: (1) a capping group, which generally containing a hydrophobic ring such as an aromatic or heterocycle group interacts with amino acids at the pocket entrance or residues on the surface of the protein. (2) a linker, which occupies the tubular channel to connect the hydrophobic ring and the zinc-binding group. (3) a zinc-binding group(ZBG), which chelates with zinc ion in the active center of HDACs, and forms hydrogen bonds with the amino acid residues of active sites [[31], [32], [33]] (see Fig. 2). Quinoxalinones are the major classes of organic compounds of great importance in chemical and pharmaceutical industries, exhibiting a broad spectrum of biological properties including anti-viral [34], anti-diabetic [35], anti-bacterial [36], anti-fungal [37], anti-malarial and anti-tumor [38]. Quinoxalinones are reported as inhibitors of aldose reductase, partial agonists of γ-aminobutyric acid (GABA/benzodiazepine receptor complex) and kinase inhibitors [39]. A number of drugs or drug candidates comprise quinoxalinone core structures highlighting their continued importance [40]. Converso et al. reported thioquinazolinones as a new Cell Cycle Checkpoint Kinase 1 (Chk1) inhibitors [41]. Chk1 could arrest the cell cycle to allow DNA repair for maintaining the stability and integrity of the cell genome. However, overexpressed Chk1 leads to cells constantly entering the cell cycle, causes DNA damage to accumulate in replication and finally results in the occurrence of malignant tumors. Chk1 inhibitors remove the blocking effect of Chk1 on cell cycle checkpoints to promote tumor cell apoptosis [42,43]. Consequently, our research group focused on combining two pharmacophores, thioquinazolinone [41] and 2-aminobenzamide. Furthermore, we designed and synthesized a series of class I HDAC selective inhibitors that comprised thioquinazolinone as the cap group and 2-aminobenzamide as the ZBG (Fig. 3).