Synthesis of Osthole- and Cinnamate-Based Hydroxamates as Histone Deacetylase Inhibitors with Promoting Neuroblastoma Cell Differentiation

• Main Authors: Ping Yang, 陽蘋
• Other Authors: Wei-Jan Huang
• Format: Others
• Language: zh-TW
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/84490496578788669090

碩士 === 臺北醫學大學 === 生藥學研究所 === 98 === Histone deacetylase (HDAC) inhibitors had been used as potential agents for targeted cancer chemotherapy. From previous publications, HDAC inhibitors were know to consist of three major parts: a hydrophobic cap for surface recognition, a zinc-chelating group and a hydrophobic linker between the two functional groups. We focus on the synthesis of osthole- and cinnamate-based hydroxamates as histone deacetylase inhibitors and test their neuronal differentiation activities on neuroblastoma cells (SH-SY5Y). Eleven novel osthole-based N-hydroxamates, compound 6a~6k, were synthesized and screened for HDAC inhibitory activity by using HeLa nuclear extract. In this screening, compounds 6c, 6d, 6g and 6k showed similar activity (the IC50 was 24.6, 28.9, 22.2 and 23.8 nM, respectively) as suberoylanilide hydroxamic acid (SAHA, the IC50 was 41.7 nM), the potent HDAC inhibitor for the treatment of cutaneous T-cell lymphoma (CTCL) approved by FDA in 2006. After screening on different classes of HDAC enzymes, our compounds were active against both class I (HDAC-1, -8) and class II (HDAC-4, -6) indicated that all of them showed similar inhibitory activity against HDAC-1, -4 and -6, but were much more active against HDAC-8, especially the compound 6c with 12-fold active than SAHA. In the docking analysis, the branched side chains, the dimthylpropane and N-hydroxypropamide groups, of compound 6c made the hydrophobic interaction on HDAC 8 stronger than that of SAHA. Furthermore, the compound 6c also showed the best cellular activity on the promotion of neurite outgrowth and neuronal differentiation on SH-SY5Y neuroblastoma cells in these series of analogues. Fourteen novel N-hydroxycinnamides, comuond 11a~11e, 17a~17f, 22, 27 and 32, substituted with ortho- or para- benzyl derivatives were synthesized and screened for their HDAC inhibitory activity (HDAC1, -4, -6, -8). Compounds 11a, 11c, 11d, 22 and 32 were highly selective against HDAC-8 and were 9-, 3-, 5-, 15- and 12-fold, respectively potent than that of SAHA. But in neuroblastoma differentiation experiment, only compounds 22 and 32 showed significant promoting effect, others lost their activity in the cell model system. By these results, we found that osthole-based hydroxamates exhibited SAHA-like activity against HDAC-1, -4, -6 and -8. and were likely a wonderful skeleton for pan HDAC inhibitor design. On the other hand, the benzyl substituted N-hydroxycinnamides were selective toward HDAC 8 over other subtypes (HDAC-1, -4, -6). We think that this skeleton might be a good lead for the design of novel HDAC inhibitor with HDAC-8 selectivity. Although the preliminary data showed that some of the compounds were effective on the promotion of the neuroblastoma differentiation, but there still further estimations needed to be done to determinate their therapeutic potential on neuroblastoma.