Natural Product Hybrid and Ortho-Biaryl N-Hydroxycinnamide as Leads for Anticancer Agent Development

Histone deacetylases (HDAC) play a role in reversible acetylation of histones, transcription factors, and other proteins, which are associated with chromatin remolding and regulation of gene expression. HDAC up-regulation can cause inappropriate gene expression associated with the pathogenesis of many forms of malignancy. Studies revealed that HDAC inhibition can induce cancer cell growth arrest, differentiation and apoptosis. Substantial preclinical evidence suggested that HDAC inhibitors combined with a diverse range of other targeted therapies or of standard chemotherapeutic agents can synergistically induce cancer cells death, demonstrating that HDAC inhibition may be more broadly effective in the treatment of cancer when integrate with other anticancer agents. To date, SAHA and FK-228 are two FDA-approved HDAC inhibitors used for hematologic malignancies. Thus, it has been validated as a promising strategy in cancer therapy. Our ongoing effort is to explore novel pan or isoform-specific HDAC inhibitors as effective anticancer agents using naturally occurring scaffold and knowledge-based design. Recently, we have achieved an aliphatic-chain hydroxamate 1k by hybridizing SAHA scaffold and indole core as a potent pan-HDAC inhibitor against several isoforms. It also exhibited multiple significant cellular effects on human cancer cells as well as antitumor activity superior to SAHA in xenograft model yet without significant side effects. Furthermore, using knowledge-based design combined with molecular modeling techniques, we have developed an N-hydroxycinnamide 9d showed excellent HDAC8 inhibition and antiproliferative activity against several human lung cancer cells comparable to PCI34051, a known HDAC8-specific inhibitor. Thus, we considered that structure optimization on compounds 1k, 9d may further improve their in vitro and in vivo pharmacological profile for clinical studies or lead to tool compounds to probe the physiological role of specific HDAC. In this three-year project, we will combine synthetic chemistry and enzyme-based assay by our lab with biological evaluation by Co-PI, Prof. Yi-Ching Wang at NCKU to achieve our goal for lead optimization based on the results as described above. This study may help us to develop potential HDAC inhibitors for anticancer therapy or for other diseases related to the enzyme. Specific aim of the first year: Exploiting indole-based aliphatic-chain hydroxamate 1k as a lead compound, we aim to use bioisosterism concept for modification to connecting constituent of linker and anilide moiety to generate five series compounds and to investigate whether such modification could improve the cytotoxicity against various human cancer cells in-vitro and in vivo. Moreover, the structure-activity relationship (SAR) could be validated through the work. Specific aim of the second year: Based on our preliminary studies on ortho-biphenyl N-hydroxycinnamide 9d, we aim to diversify biphenyl group to produce three series compounds to increase the antiproliferative potency against several human cancer cells, leading to construct the SAR. The physiological role of HDAC8 in cellular biological process could be further clarified through the study. Specific aim of the third year: Owing to the effect of compound 9d on zebrafish tissue necrosis associated with macrophage engulfment, we aim to conjugate 9d into resin at different position to obtain two series compounds as an affinity chromatography column to pull down the target. The cellular signaling related to compound 9d could be further investigated.