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  • In our previous study we designed and synthesized compounds


    In our previous study, we designed and synthesized compounds of A series from the starting material 4-hydroxy-3-methoxycinnamic Boc-D-Asp(OtBu)-OH.DCHA (ferulic acid). These compounds with R group being amino acid residues, fatty acyl group and sulfuryl group showed moderate HDAC inhibition and in vitro antitumor potency. The representative compound 1 (17a) exhibited little selectivity among HDAC1/2/3/6. Besides, using 4-hydroxycinnamic acid as the starting material, we also designed and synthesized compounds of B series. The structure-activity relationship (SAR) indicted that the compounds with benzoyl groups in R were much more potent than analogs with other substitutes including amino acid residues, fatty acyl group and sulfuryl group. What’s more, the representative compound 2 (11y) exhibited not only potent in vitro and in vivo antitumor activity but also dual selectivity against HDAC1/3. Herein, inspired by the SAR of B series compounds, it is possible that replacing the valproyl group of compound 1 with different substituted benzoyl groups will lead to more potent 4-hydroxy-3-methoxycinnamic acid-based analogs. And it is also very interesting to investigate if the introduction of 3-methoxy group will change the HDACs isoform selective profile of compound 2 (Fig. 2).
    Results and discussion
    Conclusion In summary, a novel series N-hydroxybenzamide-based HDACIs were designed, synthesized and evaluated. Most compounds displayed excellent HDAC inhibitory activity than the positive control SAHA, especially 6q and 6t with single digit-nanomolar IC50 values. Compounds 6i, 6k, 6q and 6t with potent HDAC inhibitory activity exhibited superior antiproliferative activity than SAHA. Comparison of the HDACs isoform selectivity of the 4-hydroxy-3-methoxycinnamic acid-based compounds (1, 6t) and the 4-hydroxycinnamic acid-based compounds (2, 7, 8, 9) indicated that, for these N-hydroxycinnamamide-based HDACIs, the 3-methoxy group in linker part and the R group in cap part could cooperatively fine-tune their HDAC isoform selectivity.
    Experiment sections
    Introduction Osteoarthritis (OA), the most common form of joint disease, is associated with cartilage degradation, disability and poor quality of life and is a leading cause of chronic disability in middle-aged and older populations affecting more than 27 million Americans [1]. Aging is a major risk factor for OA, however other factors such as gender, obesity, joint injury, genetics and mechanical abnormalities have been shown to contribute to the development of OA [2]. There is no single specific cause that has been identified for OA till date, however, there is a growing body of evidence that suggest that OA is a result of the interactions between molecular events and mechanical issues in the affected joint [3]. Although OA is a disease of the whole joint and affect all the joint tissues, cartilage degradation is the main characteristic of OA [4]. The underlying molecular mechanisms of OA pathogenesis involve multiple components and include dysregulation of different layers of regulatory mechanisms. Altered gene expression of matrix degrading proteases (MMPs), inflammatory mediators and extracellular matrix (ECM) related genes such as collagens and proteoglycans in articular chondrocytes isolated from OA cartilage has been documented [4], [5], [6], [7], [8]. However, the underlying regulatory mechanism for the expression of these genes in OA cartilage has not been fully understood. Epigenetics is an important layer of regulation of gene expression and is associated with the pathogenesis of a number of human diseases [9]. Epigenetics is defined as a stable change in gene expression between cell divisions, and sometimes generations, that involves no change in the underlying DNA sequence [10]. The “NIH Roadmap Epigenomics Project” defined epigenetics as heritable changes in gene activity and expression and stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable [11]. Here we reviewed the recent findings in this field with an emphasis on the potential of HDACs inhibitors for the management of OA. If we have missed a reference, it is inadvertent and not because the findings are not important.