Abstract
Vorinostat (SAHA) with great therapeutic potential has been approved by the FDA for the treatment of cutaneous T-cell lymphoma as the first HDACs inhibitor, but the drawbacks associated with hydroxamic acid group (poor stability, easy metabolism, weak binding ability to class IIa isozymes, and poor selectivity) have been exposed during the continuous clinical application. Based on the pharmacophore of HDAC inhibitors, two series of compounds with novel zinc binding group (ZBG) were designed and synthesized, and the antitumor bioactivities were evaluated in four human cancer cell lines (A549, Hela, HepG2, and MCF-7). Among the synthesized compounds, compounds a6, a9, a10, b8, and b9 exhibited promising inhibitory activities against the selected tumor cell lines, especially compounds a9 and b8 on Hela's cytostatic activity (a9: IC50 = 11.15 ± 3.24 μM; b8: IC50 = 13.68 ± 1.31 μM). The enzyme inhibition assay against Hela extracts and HDAC1&6 subtypes showed that compound a9 had a certain broad-spectrum inhibitory activity, while compound b8 had selective inhibitory activity against HDAC6, which was consistent with Western blot results. In addition, the inhibitory mechanism of compounds a9 and b8 in HDAC1&6 were both compared through computational approaches, and the binding interactions between the compounds and the enzymes target were analyzed from the perspective of energy profile and conformation. In summary, the compounds with novel ZBG exhibited certain antitumor activities, providing valuable hints for the discovery of novel HDAC inhibitors.
Highlights
Cancers with increasing incidence and mortality have been the leading cause of death, seriously threating the public health and making the design and discovery of chemotherapeutic agents important (Evans et al, 2017)
With the continuous development of epigenetic mechanisms, the increasing evidence suggests that the epigenetic dysregulation of gene expression interacts extensively with the tumor initiation and progression (Connolly and Stearns, 2012; New et al, 2012; Seidel et al, 2012; Abdelfatah et al, 2016), which can be comprehensively investigated as a novel anticancer drug development strategy
Epigenetic modifications refer to the heritable alterations in gene expression unrelated to the DNA sequences, and the histone acetylation catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs) has become a major component of epigenetic research field (Glozak and Seto, 2007; Kouzarides, 2007; Zhang et al, 2017)
Summary
Cancers with increasing incidence and mortality have been the leading cause of death, seriously threating the public health and making the design and discovery of chemotherapeutic agents important (Evans et al, 2017). With the continuous development of epigenetic mechanisms, the increasing evidence suggests that the epigenetic dysregulation of gene expression interacts extensively with the tumor initiation and progression (Connolly and Stearns, 2012; New et al, 2012; Seidel et al, 2012; Abdelfatah et al, 2016), which can be comprehensively investigated as a novel anticancer drug development strategy. Epigenetic modifications refer to the heritable alterations in gene expression unrelated to the DNA sequences, and the histone acetylation catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs) has become a major component of epigenetic research field (Glozak and Seto, 2007; Kouzarides, 2007; Zhang et al, 2017). Unlike the modification in DNA sequence, the epigenetic changers are reversible, showing great potential in targeting epigenetic regulation of gene for the discovery of new anticancer agents
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