合成以吲哚為基礎之氮-羥基肉桂酸醯胺作為組蛋白去乙醯酶抑制劑

Synthesis of Indole-Based N-Hydroxycinnamide as Inhibitors of Histone Deacetylase

李欣穎(Hsin-Ying Li)

指導教授 ： 黃偉展

臺北醫學大學/藥學院/生藥學研究所/碩士(2011年)

https://doi.org/10.6831/TMU.2011.00146

摘要

組蛋白去乙醯酶抑制劑為目前癌症標靶治療研究發展趨勢之一，其化學結構主要分為三部份：與鋅產生螯合之基團、疏水性鏈長以及疏水性辨認部位。本研究主要合成以吲哚為基礎之氮-羥基肉桂酸醯胺作為組蛋白去乙醯酶抑制劑。

以氮-羥基肉桂酸醯胺為模板，在不同之取代位向藉由不同碳鏈長度結合不同取代基之吲哚環，合成系列化合物6a-6i、6j-6k及10、15，以子宮頸癌細胞萃取之組蛋白去乙醯酶(HeLa nuclear HDAC)測試其活性，其中抑制活性最好之化合物6e、6l、6n，對於第一與第六型(HDAC-1, -6)組蛋白去乙醯酶之抑制活性與SAHA相當，而在第四及第八型(HDAC-4, -8)組蛋白去乙醯酶抑制活性中，均顯示較SAHA強之活性；而抑制活性最差之化合物6a、6b、6c，對於第一與第四型(HDAC-1, -4)組蛋白去乙醯酶之抑制效果亦均較SAHA差，而對於第八型(HDAC 8)組蛋白去乙醯酶之抑制活性則較SAHA強20倍以上，有潛力發展為選擇性第八型組蛋白去乙醯酶抑制劑。

在細胞抑制實驗中，化合物6n (GI50=0.13 μM)對於PC3細胞之抑制效果明顯強於SAHA (GI50=0.61 μM)，證實以吲哚為基礎之氮-羥基肉桂酸醯胺之化合物6n具有發展為有效組蛋白去乙醯酶抑制劑抗癌藥物之潛力。

關鍵字

組蛋白去乙醯酶抑制劑 ； 癌症 ； 合成 ； 吲哚肉桂酸醯胺

並列摘要

Histone deacetylase (HDAC) inhibitors have been validated as a potential agent for targeted cancer chemotherapy. The pharmacophore of reported HDAC inhibitor is composed of three moieties: a zinc-chelating group, a connection group consisting of linear or cyclic linker, and a hydrophobic cap for surface recognition. In this study, we have performed chemical synthesis and biological evaluation of indole-based N-Hydroxycinnamidesas series as histone deacetylase inhibitors.

Seventeen novel N-hydroxycinnamides capped with substituted-indole (compounds 6a~6i, 6j~6o and 10, 15) were synthesized in order to achieve structure optimization and screened for inhibitory activity against HeLa nuclear HDACs. Compound 6e, 6l, and 6n with potent nuclear HDACs inhibition showed not only SAHA-like activity towards HDAC-1,-6 inhibition, but also superior activity over SAHA against HDAC-4, -8 by about 6-, 10-fold difference, respectively. Interestingly, compounds 6a, 6b and 6c exhibited weak inhibitory activities against HeLa nuclear HDACs while showing superior inhibitory activities against HDAC 8 over other isoforms (HDAC1, -4, -6).

Further antiproliferative activity demonstrated that compound 6n showed strong cytotoxicity against PC3 (GI50=0.13 μM) comparable to that of SAHA (GI50=0.61 μM). This study suggested that indole-based N-hydroxycinnamide 6n, a potent histone deacetylase inhibitor, has the potential to develop as an anticancer agent.

並列關鍵字

Histone Deacetylase Inhibitors ； cancer ； synthesi ； indole cinnamide

參考文獻

1.Seddon BM, Workman P: The role of functional and molecular imaging in cancer drug discovery and development. Br J Radiol 2003, 76 Spec No 2:S128-138.

2.Sikora K, Advani S, Koroltchouk V, Magrath I, Levy L, Pinedo H, Schwartsmann G, Tattersall M, Yan S: Essential drugs for cancer therapy: a World Health Organization consultation. Ann Oncol 1999, 10(4):385-390.

3.Walkinshaw DR, Yang XJ: Histone deacetylase inhibitors as novel anticancer therapeutics. Current Oncology 2008, 15(5):237-243.

4.Luger K, Mader AW, Richmond RK, Sargent DF, Richmond TJ: Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 1997, 389(6648):251-260.

6.Santos-Rosa H, Caldas C: Chromatin modifier enzymes, the histone code and cancer. Eur J Cancer 2005, 41(16):2381-2402.