新型组蛋白去乙酰化酶抑制剂的设计、合成及活性评价: 含硫锌离子结合基团的发现

doi:10.5246/jcps.2019.06.040

中国药学(英文版) ›› 2019, Vol. 28 ›› Issue (6): 408-421.DOI: 10.5246/jcps.2019.06.040

新型组蛋白去乙酰化酶抑制剂的设计、合成及活性评价: 含硫锌离子结合基团的发现

程文文¹, 张冬梅², 郑强¹, 李中军¹, 孟祥豹^1*

1. 北京大学医学部药学院天然药物及仿生药物国家重点实验室, 北京 100191
2. 山东省食品药品检验研究院, 山东济南 250101

收稿日期:2019-04-02 修回日期:2019-05-10 出版日期:2019-06-30 发布日期:2019-05-15
通讯作者: Tel.: +86-010-82801714, E-mail: xbmeng@bjmu.edu.cn
基金资助:
National Natural Science Foundation of China (Grant No. 81573272).

Design, synthesis and biological evaluation of novel HDAC inhibitors: sulphur-containing zinc binding groups

Wenwen Cheng¹, Dongmei Zhang², Qiang Zheng¹, Zhongjun Li¹, Xiangbao Meng^1*

1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
2. Shandong Institute for Food and Drug Control, Jinan 250101, China

Received:2019-04-02 Revised:2019-05-10 Online:2019-06-30 Published:2019-05-15
Contact: Tel.: +86-010-82801714, E-mail: xbmeng@bjmu.edu.cn
Supported by:
National Natural Science Foundation of China (Grant No. 81573272).

摘要/Abstract

摘要：

锌离子结合基团是组蛋白去乙酰化酶(HDAC)抑制剂结构中的关键部分。本文中设计了一系列含硫的基团, 替换了SAHA中的羟肟酸以及BML-210中的苯甲酰胺等经典的锌离子结合基团, 合成了新的HDAC抑制剂。经过对HDAC抑制活性的测试及构效关系分析, 最终发现了一类富含硫的基团(二乙胺基二硫代过硫甲酸酯)是新的有效锌离子结合基团。在所有合成的化合物中, 4d显著优于BML-210, 对HDAC的亚型1,2的抑制活性与SAHA相当, 被选为先导化合物。

关键词: 组蛋白去乙酰化酶抑制剂, 锌离子结合基团, 抗肿瘤

Abstract:

Zinc binding group (ZBG) is the crucial moiety in the chemical structure of any HDAC inhibitor. In the present study, a series of sulphur-containing ZBG were designed and synthesized in the novel HDAC inhibitors to replace the classical ZBGs of SAHA and BML-210,hydroxamic acids and benzamides, respectively. The HDAC inhibitory activity and the structure-activity relationships of these molecules were analyzed. A sulphur-rich group, diethylcarbamo (dithioperoxo)thioate, was finally identifiedas a novel potent ZBG. Among all the synthesized compounds, 4d was much more potent compared with BML-210, and it showed similar inhibitory effect of SAHA against HDAC isoforms 1 and 2. Therefore, it was chosen as a lead compound.

Key words: Histone deacetylase inhibitor, Zinc binding group, Anticancer

中图分类号:

R914

Supporting:

程文文, 张冬梅, 郑强, 李中军, 孟祥豹. 新型组蛋白去乙酰化酶抑制剂的设计、合成及活性评价: 含硫锌离子结合基团的发现 [J]. 中国药学(英文版), 2019, 28(6): 408-421.

Wenwen Cheng, Dongmei Zhang, Qiang Zheng, Zhongjun Li, Xiangbao Meng. Design, synthesis and biological evaluation of novel HDAC inhibitors: sulphur-containing zinc binding groups[J]. Journal of Chinese Pharmaceutical Sciences, 2019, 28(6): 408-421.

参考文献

[1] Roche, J.; Bertrand, P. Inside HDACs with more selective HDAC inhibitors. Eur. J. Med. Chem. 2016, 121, 451-483.

[2] Li, Z.M.; Zhu, W.G. Targeting histone deacetylases for cancer therapy: from molecular mechanisms to clinical implications. Int. J. Biol. Sci. 2014, 10, 757-770.

[3] Hou, J.L.; Li, Z.H.; Fang, Q.H.; Feng, C.R.; Zhang, H.W.; Guo, W.K.; Wang, H.H.; Gu, G.X.; Tian, Y.P.; Liu, P.; Liu, R.H.; Lin, J.P.; Shi, Y.K.; Yin, Z.; Shen, J.; Wang, P.G. Discovery and extensive in vitro evaluations of NK-HDAC-1: a chiral histone deacetylase inhibitor as a promising lead. J. Med. Chem. 2012, 55, 3066-3075.

[4] Patil, V.; Sodji, Q.H.; Kornacki, J.R.; Mrksich, M.; Oyelere, A.K. 3-Hydroxypyridin-2-thione as novel zinc binding group for selective histone deacetylase inhibition. J. Med. Chem. 2013, 56, 3492-3506.

[5] Eckschlager, T.; Plch, J.; Stiborova, M.; Hrabeta, J. Histone deacetylase inhibitors as anticancer drugs. Int. J. Mol. Sci. 2017, 18, E1414.

[6] Shen, S.D.; Kozikowski, A.P. Why hydroxamates May not be the best histone deacetylase inhibitors-what some May have forgotten or would rather forget? Chem. Med. Chem. 2016, 11, 15-21.

[7] Bora-Tatar, G.; Dayangaç-Erden, D.; Demir, A.S.; Dalkara, S.; Yelekçi, K.; Erdem-Yurter, H. Molecular modifications on carboxylic acid derivatives as potent histone deacetylase inhibitors: Activity and docking studies. Bioorg. Med. Chem. 2009, 17, 5219-5228.

[8] Nagaoka, Y.; Maeda, T.; Kawai, Y.; Nakashima, D.; Oikawa, T.; Shimoke, K.; Ikeuchi, T.; Kuwajima, H.; Uesato, S. Synthesis and cancer antiproliferative activity of new histone deacetylase inhibitors: hydrophilic hydroxamates and 2-aminobenzamide-containing derivatives. Eur. J. Med. Chem. 2006, 41, 697-708.

[9] Gu, W.X.; Nusinzon, I.; Smith, R.D. Jr, Horvath, C.M.; Silverman, R.B. Carbonyl- and sulfur-containing analogs of suberoylanilide hydroxamic acid: Potent inhibition of histone deacetylases. Bioorg. Med. Chem. 2006, 14, 3320-3329.

[10] Wang, L.; Zhang, J.Y.; Kim, B.; Peng, J.J.; Berry, S.N.; Ni, Y.; Su, D.D.; Lee, J.; Yuan, L.; Chang, Y.T. Boronic acid: A bio-inspired strategy to increase the sensitivity and selectivity of fluorescent NADH probe. J. Am. Chem. Soc. 2016, 138, 10394-10397.

[11] Suzuki, T.; Matsuura, A.; Kouketsu, A.; Hisakawa, S.; Nakagawa, H.; Miyata, N. Design and synthesis of non-hydroxamate histone deacetylase inhibitors: identification of a selective histone acetylating agent. Bioorg. Med. Chem. 2005, 13, 4332-4342.

[12] De-Vreese, R.; D'hooghe, M. Synthesis and applications of benzohydroxamic acid-based histone deacetylase inhibitors. Eur. J. Med. Chem. 2017, 135, 174-195.

[13] Wang, J.J.; Shen, Y.K.; Hu, W.P.; Hsieh, M.C.; Lin, F.L.; Hsu, M.K.; Hsu, M.H. Design, synthesis, and biological evaluation of pyrrolo[2, 1-c][1, 4]benzodiazepine and indole conjugates as anticancer agents. J. Med. Chem. 2006, 49, 1442-1449.

[14] Obermoser, V.; Urban, M.E.; Murgueitio, M.S.; Wolber, G.; Kintscher, U.; Gust, R. New telmisartan-derived PPARγ agonists: Impact of the 3D-binding mode on the pharmacological profile. Eur. J. Med. Chem. 2016, 124, 138-152.

[15] Wang, R.B.; Chen, C.S.; Zhang, X.J.; Zhang, C.D.; Zhong, Q.; Chen, G.L.; Zhang, Q.; Zheng, S.L.; Wang, G.D.; Chen, Q.H. Structure-activity relationship and pharmacokinetic studies of 1,5-diheteroarylpenta-1,4-Dien-3-ones: A class of promising curcumin-based anticancer agents. J. Med. Chem. 2015, 58, 4713-4726.

[16] Giannini, G.; Vesci, L.; Battistuzzi, G.; Vignola, D.; Milazzo, F.M.; Guglielmi, M.B.; Barbarino, M.; Santaniello, M.; Fantò, N.; Mor, M.; Rivara, S.; Pala, D.; Taddei, M.; Pisano, C.; Cabri, W. ST7612AA1, a thioacetate-ω(γ-lactam carboxamide) derivative selected from a novel generation of oral HDAC inhibitors. J. Med. Chem. 2014, 57, 8358-8377.

[17] Zhang, S.J.; Hu, W.X. Synthesis, antiproliferation, and docking studies of N-phenyl-lipoamide and 8-mercapto-N-phenyloctanamide derivatives: effects of C6 position thiol moiety. Med. Chem. Res. 2012, 21, 3312-3320.

[18] Cilibrasi, V.; Tsang, K.; Morelli, M.; Solfa, F.; Wiggins, H.L.; Jones, A.T.; Westwell, A.D. Synthesis of substituted carbamo(dithioperoxo)thioates as potential BCA2-inhibitory anticancer agents. Tetrahedron Lett. 2015, 56, 2583-2585.

[19] Villadsen, J.S.; Stephansen, H.M.; Maolanon, A.R.; Harris, P.; Olsen, C.A. Total synthesis and full histone deacetylase inhibitory profiling of Azumamides A-E as well as β²- epi-Azumamide E and β³-epi-Azumamide E. J. Med. Chem. 2013, 56, 6512-6520.

[20] Wang, J.J.; Shen, Y.K.; Hu, W.P.; Hsieh, M.C.; Lin, F.L.; Hsu, M.K.; Hsu, M.H. Design, synthesis, and biological evaluation of pyrrolo[2,1-c][1,4]benzodiazepine and indole conjugates as anticancer agents. J. Med. Chem. 2006, 49, 1442-1449.

新型组蛋白去乙酰化酶抑制剂的设计、合成及活性评价: 含硫锌离子结合基团的发现

Design, synthesis and biological evaluation of novel HDAC inhibitors: sulphur-containing zinc binding groups

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价

[1]	刘良裕, 杨宇珂, 杜肖, 吴桐, 王建农. 白英中三个未被报道的甾体糖苷生物碱及其抗肿瘤活性[J]. 中国药学(英文版), 2022, 31(3): 192-201.
[2]	许士琪, 朱礼岩, 郝超, 刘文倩, 陈成龙, 陈泳怡, 刘爱芹. 一种新型含氨基酸基团替加氟前药的合成及其抗肿瘤活性评价[J]. 中国药学(英文版), 2021, 30(9): 743-753.
[3]	黄聪, 吴霭琳, 海沙尔江·吾守尔, 徐子悦, 张逸晨, 管晓东, 史录文. 中国浙江省级医保报销对于靶向抗肿瘤药使用的影响: 一项带对照的间断时间序列分析[J]. 中国药学(英文版), 2021, 30(7): 590-597.
[4]	汪子翔, 张宜凡, 杜望春, 陈群力, 姚虹, 赵梅. 天然产物通过调节活性氧水平防治肿瘤的研究进展[J]. 中国药学(英文版), 2021, 30(6): 455-467.
[5]	宋慧慧, 向卓, 薛淑一, 苗青, 赵丽艳, 李明春. 白头翁皂苷及其单体抗肿瘤作用及机制的研究进展[J]. 中国药学(英文版), 2021, 30(5): 381-392.
[6]	刘曼, 张爽, 李卓越, 王光雪, 王景茹, 张烜. 氧化锌纳米粒的制备与表征[J]. 中国药学(英文版), 2020, 29(9): 617-625.
[7]	周北斗, 俞紫涵, 童玉贵, 李佳莉, 黄堡城, 魏蓉蓉, 翁智敏, 王欣, 阮志鹏, 林健, 许彩红, 刘建波. 异戊烯基和香叶基取代的呫吨酮的合成与生物活性研究[J]. 中国药学(英文版), 2020, 29(8): 564-576.
[8]	周北斗, 王欣, 翁智敏, 黄堡城, 马泽通, 于博, 阮丽琴, 胡栋宝. 氧杂蒽酮的合成和抗肿瘤、抑制酪氨酸酶和抑制血小板聚集活性研究[J]. 中国药学(英文版), 2019, 28(4): 247-256.
[9]	郝艳丽, 钟婷, 杜若, 张华, 刘碧林, 张烜. 包载共轭亚油酸-紫杉醇的iRGD修饰的含溶血磷脂的温敏脂质体的细胞摄取和抗肿瘤药效[J]. 中国药学(英文版), 2019, 28(2): 121-133.
[10]	卢东渤, 陈宇, 刘姗, 郭超, 李霞, 李中军, 孟祥豹. 茚[1, 2-b]并吲哚衍生物的合成、双重抑制拓扑异构酶I和II及逆转多重耐药等生物活性研究[J]. 中国药学(英文版), 2019, 28(11): 786-801.
[11]	雷丽, 陈宇, 杨思敏, 孟祥豹, 余四旺. 一个新型氮杂萘醌类化合物通过诱导细胞凋亡来抑制肿瘤生长[J]. 中国药学(英文版), 2018, 27(9): 600-607.
[12]	周林光, 江滨. 用于强直性脊柱炎的抗肿瘤坏死因子(TNF-α)抑制剂的临床应用进展[J]. 中国药学(英文版), 2018, 27(1): 59-63.
[13]	朱刚直, 易勤, 范志宏, 马岳慧, 王丹丹, 王磊, 程泽能. LC-MS/MS法测定大鼠血浆中PAC-1的新型抗癌衍生物的浓度及其药物动力学研究[J]. 中国药学(英文版), 2017, 26(11): 811-818.
[14]	陈加贝, 郑育奋, 孔维崎, 李鑫, 罗来春, 韩彦君, 林松文, 孙崎, 葛泽梅, 李润涛. 环状磷酰胺氮芥-喹唑啉偶联物的设计、合成及抗肿瘤活性[J]. 中国药学(英文版), 2017, 26(10): 727-736.
[15]	梁晓霞, 孔令茜, 何敏. 从卵叶蜘蛛抱蛋中分离得到的一个具有潜在抗菌活性的高异黄酮类化合物[J]. 中国药学(英文版), 2016, 25(9): 700-703.