| Nowadays, people have realized that genetic diseases are involved with epigenetic abnormalities. Histone modification, as a significant aspect of epigenetic mechanisms, has great influence on the process of cancer development. People have discovered several kinds of enzymes involved in histone modification. Among them, histone deacetylases (HDACs) and histone acetyltransferases (HATs) work together in dynamic balance as a system in the nucleus and play key roles in chromosome structure modification as well as gene expression regulation. Therefore HDACIs which possess efficient antitumor activity can induce tumor cell apoptosis, inhibit the microvascular formation and lower the migrating. Up to date, there are dozens of HDACIs in various clinical trails, including four drugs approved by US FDA and one approved by CFDA, which no doubtly will provide more choices and effective anti-tumor treatments for patients.Panobinostat (LBH-589), as the first pan-HDACI developed by Novartis, which may slow the plasma cells of multiple myeloma patients with excessive development or kill these virulent cells in the process of inhibiting to HDACs, was approved by US FDA for the treatment of multiple myeloma in February 2015. Clinical studies revealed that Panobinostat had a good performance on multiple myeloma patients, which made it a pressing demand in the treatment of multiple myeloma. The synthetic routes of Panobinostat have been analyzed and optimized by extensive literature investgation. Based on molecular combination and classical pharmacophore model, we regarded Panobinostat as lead compound, and introduced N1-hydroxyterephthalamide as active fragment. Finally, we designed and synthesized a series of N1-hydroxyterephthalamide HDACIs with indole cap group.According to the preliminary in vitro evaluation, the chain length seemed to impact the potency dramatically with the shorter chain analog 8b being more potent within the aliphatic amide analogs. Notably, aromatic amide analogs overall exhibited better inhibitory activities. When the substitution pattern was compared within this series, the para-substitutents gave more potent analogs. This may suggest that the optimal size and substitutional position are needed to produce optimal interactions with proteins and consequently affect the inhibitory activities. Upon the results of the enzymatic inhibition, compound 12m showed better inhibitory activity comparing with the control drug SAHA, which was also verified by further molecular docking studies in the crystal structure of HDAC2. To further ascertain HDAC isoform-selectivity of 12m, we conducted enzymatic inhibitory assays against HDAC1 (Class Ⅰ), HDAC8 (Class Ⅰ), HDAC6 (Class Ⅱb), HDAC4 (Class Ⅱa), and HDAC11 (Class Ⅳ). Compound 12m exhibited almost no inhibition to HDAC4 at the concentration of 100 μM and displayed ICso values close to the magnitude of micromole or nanomole versus other HDAC isoforms, which demonstrated that 12m showed similar overall selectivity profile with control PXD101. In the following research, we conducted in vitro antiproliferative evaluation of target compounds in cellular assays.4 compounds (8d, 12d,12j and 12m) selected by preliminary antiproliferative screening exhibited comparable potency to SAHA in suppressing the growth of HL60 cells, but less inhibitory activities aganist other cell lines than the positive control SAHA. We are looking forward to develop HDACIs with excellent HDACs inhibitory activities and isoform selectivity by further research and exploration for the N1-hydroxyterephthalamide derivatives. |
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