Development of Novel HDAC Inhibitors from Natural Products and Studies on Their Biological Activities

Nucleosomes contain an average of 150 base pairs of DNA wrapped around the nucleosomal core of histones in 1.75 turns of left-handed superhelical DNA. Four histones (H2A, H2B, H3, and H4) are subjected to a variety of enzyme-catylzed posttranslational modifications to modulate the function of chromatin. Among all modifications, acetylation has been studied most extensively. Histones can be reversibly acetylated and deacetylated on the ε-amino group of lysine residues, which is dominated by the opposing activities of two types of enzymes, HAT (hydroxylysine acetyltransferase) and HDAC (hydroxylysine deacetylase), respectively. A balance between acetylation and deacetylation may result in the regulation of chromatin function and gene expression. Aberrant regulation of this epigenetic system has been shown to cause inappropriate gene expression, a key event in the pathogenesis of many forms of cancer. Further evidence indicated that HDAC inhibitor (HDACi) can trigger cell growth arrest, differentiation, and apoptosis in many types of tumor cells by reactivating the transcription of a small number of genes. Normal cells are less susceptible than transformed cells to the antiproliferative effect of HDAC inhibitors. Hence, these enzymes have been identified as attractive targets for cancer therapy. We recently reported that a prenylflavone (propolin G), isolated from Taiwanese propolis, can induce caspase-dependent apoptosis in brain cancer cells. Moreover, we have developed a practical method to isolated large amount of Propolin G from botanical origin of propolis. Thus, it can provide us a sufficient resource for chemical modifications. A hydrated prenylflavanone (NBM-TP-007-GS-002, patent in reviewing) was prepared via a facile semi-synthetic method from propolin G and evaluated its anti-cancer activity. Our preliminary data indicated NBM-TP-007-GS-002 can inhibit brain cancer cells growth via the inhibition of HDAC. In this three-year project, we will further combine the field of natural products isolation, drug synthesis and biochemical mechanism studies to optimize the anti-HDACs activity based on the structure of NBM-TP-007-GS-002. Thus, it can provide us a scope to develop a novel drug for the treatment of cancer and other diseases related to HDACs. Specific aim of the first year: Using propolin G from botanical origin of Taiwanes propolis as a lead structure, we aim to apply the semi-synthetic methodology to prepare a series of flavone based analogs. The structure and activity relationship of these agents for HDACi activities can be preliminary elucidated through this work. Specific aim of the second year: Based on the understanding of the structure and activity relationship against HDACs from the first year, we aim to apply the total synthetic strategy to prepare a series of chalcone based analogs to mimic our lead compound. Moreover, we will investigate the cellular signal transduction regulation of these compounds described above. Specific aim of the third year: In order to develop a potent HDACi, we aim to design a series of aroylbenzofuran scaffold based analogs to investigate their structure and activity relationship. This work will be valuable for developing a targeted therapy drug for the treatment of cancers.