| Summary: | 碩士 === 臺北醫學大學 === 生藥學研究所 === 102 === Histone deacetylase (HDAC) inhibitors are regarded as a promising therapeutic for treatment of cancer. However, current HDAC inhibitors have some unsatisfactory problems, including limited potency for solid tumors and dose-limiting side effects. This study includes： I. Aliphatic Hydroxamates Capped with Substituted Aryl Indole as Histone Deacetylase Inhibitors against Cancer Cells; II. Structure Optimization for Ortho-Aryl N-Hydroxycinnamides as HDAC8 Isoform-Selective Inhibitors I. Currently, SAHA and Romidepsin both were FDA-approved HDAC inhibitors to treat Cutaneous T cell lymphoma (CTCL). Depite their success in hematopoietic malignancy, HDAC inhibitors in clinical trials had still failed to heal solid tumorsm, thus, encouraging us to develop novel inhibitors against these tumors. The pharmacophore of SAHA is composed of three parts such as a zinc-binding group, a hydrophobic linker and a surface recognition cap. In this study, we used aryl indole as a surface recognition cap to develop a novel series of HDAC inhibitors. All compounds were screened for HeLa nucleus HDACs enzyme inhibition. Among them, compounds 4a, 4b, 4d and 6 exhibited potent inhibitory activity (IC50 = 209, 117, 104, 232 nM) comparable to SAHA (IC50 = 275 nM). Notably, compound 4d had the best cytotoxicity against non-small-cell lung carcinoma A549 cells (GI50 = 0.65 μM) compared to SAHA (GI50 = 1.50 μM). Western
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blot analysis related to intracellular HDAC inhibiton indicated compounds 4a, 4c, and 4d had significant effect on enhancing acetylation histone H3 and p21 in HT29 cells comparable to SAHA. Further molecular docking of 4d and SAHA interacted to histone deacetylase like protein (HDLP) demonstrated that the benzenesulfonyl of compound 4d may offer more interaction with the enzyme surface at HDAC than SAHA.Cutaneous T cell lymphoma (CTCL) II. HDAC family comprises eighteen isofirms. Studies had revealed that selective HDAC inhibitors may have less side effects than pan ones. We had delveloped a lead ortho-biphenyl N-hydroxycinnamide A22d with potent HDAC8 inhibition. Based on the molecular docking result for A22d with HDAC8, we extensively added different function groups to biphenyl moiety to enhance their enzyme inhibitory activity. Seven novelly synthesized compounds were screened for anti-HDAC 8 activity and compound 11d showed the best activity (IC50 = 29.3 nM) comparable to PCI-34051 (IC50 = 27.1 nM), a reportedly potent HDAC8 inhibitor. Molecular docking analysis suggested compound 11d may interact with HDAC 8 in a specific sub-pocket which allows to provide selectivity toward HDAC 8. Furthermore, based on the potent cytotoxicity by our previously developed HDAC 8 inhibitor A5e against tumor cells, we synthesized seven additional novel inhibitors. Of these, compounds 21 and 25 had moderate HDAC 8 inhibitory activity (IC50 = 292.5, 341.2 nM). Further cellular effects of HDAC 8 inhibitors in this study are being undertaken.
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