Design, Synthesis And Preliminary Bioactivity Evaluations Of Substituted Quinoline Hydroxamic Acid Derivatives As Novel Histone Deacetylase (HDAC) Inhibitors

The histone acetylation status plays an essential role in initiation and progression of tumor among the complex epigenetic regulations. The imbalance between histone acetylation and deacetylation in cells will lead to changes in cell cycle and metabolism profile, which in turn trigger the formation of tumors. Histone deacetylases (HDACs) are important enzymes regulating the balance of acetylation and deacetylation of histones and non-histone proteins, by catalyzing hydrolysis of ε-amide bond of lysine residues. The overexpression of HDACs suppresses gene transcription and lead to silencing of tumor suppressor genes. Thus, HDAC inhibitors (HDACi) are considered a new class of more effective anticancer agents.To date, three HDAC inhibitors (Vorinostat, Romidepsin and Belinostat) have approved for the clinical therapy of cutaneous T-cell lymphoma (CTCL) or peripheral T-cell lymphoma (PTCL) by FDA. Meanwhile, more than 20 promising HDAC inhibitors are in clinical or pre-clinical studies for the treatment of various cancers.So, it powerfully demonstrates the feasibility and effectiveness of HDACs inhibitors for the treatment of cancer. Therefore, the development of new effective HDACs inhibitors is challenging topic in anticancer drugs research.According to the crystal structure of HDAC2 recently reported, combined with our previous studies on tetrahydroisoquinoline-based HDAC inhibitors, and Moffat found that CHR-3996 bearing a 6-fluoro in quinoline generated potent HDAC inhibitors against different tumor cell lines. But there are few reports about the structure activity relationship of different substituted HDAC inhibitors based on quinoline derivates. Thus, according to the isostere principle, quinoline ring was used as the enzyme surface recognition area, and a series of quinoline HDACi was designed to research on effect of the quinoline ring substituents on HDAC inhibitory activity.We have synthesized 74 new compounds, including 27 new target compounds and 47 new intermediate compounds. All the new compounds were identified through 1H-NMR,13C-NMR and mass spectrometry or other methods. The bioactivities of target compounds were evaluated in enzymatic and cellular assays.The study found that most of the target compounds had a certain HDAC inhibitory activity, which was equal to SAHA or greater. SAR show:substituents on the C4-position of quinoline ring decrease the enzyme inhibitory activity, and introducing substituents to the C6-position of quinoline ring could enhance the enzyme inhibitory activity. The potency of compound 9w (IC50=85 nM) with a bromine-substituent, was the best and more potent than SAHA (IC50=161 nM). When introducing benzene ring into C6-position, inhibitory activity decreased, indicating that the bulky substituent was not appropriate choice on C6-position. In terms of the anti-proliferation inhibition data, all tested compounds displayed obvious anti-proliferative activities compared with SAHA. Moreover, MDA-MB-231 was the most sensitive to our quinoline derivatives HDAC inhibitors and 9w showed best inhibitory potency compared with SAHA. In addition,9y exhibited most potent anti-proliferative activities in PC-3, K562 and A549 cell lines.