药学学报, 2018, 53(10): 1696-1704
引用本文:
祁宝辉, 杨颖, 宫帼唯, 何欢, 岳续朋, 徐昕, 王雅溶. 含芳氧吡啶酮结构片段的噻唑啉酮脲衍生物的设计、合成及抗肿瘤活性研究[J]. 药学学报, 2018, 53(10): 1696-1704.
QI Bao-hui, YANG Ying, GONG Guo-wei, HE Huan, YUE Xu-peng, XU Xin, WANG Ya-rong. Design, synthesis and study of anti-tumor activity of thiazolinone urea derivatives bearing aryloxypyridinone fragments[J]. Acta Pharmaceutica Sinica, 2018, 53(10): 1696-1704.

含芳氧吡啶酮结构片段的噻唑啉酮脲衍生物的设计、合成及抗肿瘤活性研究
祁宝辉, 杨颖, 宫帼唯, 何欢, 岳续朋, 徐昕, 王雅溶
遵义医学院珠海校区生物工程系, 广东 珠海 519041
摘要:
本文以cabozantinib为先导物,基于已有的c-Met激酶抑制剂的构效关系,设计并合成了13个结构新颖的小分子抑制剂,其结构经1H NMR、13C NMR和HR-MS确证。采用MTT法对所合成的化合物进行了体外抗肿瘤活性测试,采用实时动态活细胞成像法和流式细胞术对体外抗肿瘤作用机制进行了初步研究。结果表明,所设计的大多数化合物对人非小细胞肺癌细胞A549和人结直肠癌细胞HT-29有较好的抑制作用,活性优于cabozantinib;化合物对HT-29细胞除具有明显的杀伤作用外,还可抑制其增殖,促进细胞凋亡。
关键词:    芳氧吡啶酮      噻唑啉酮脲      设计      合成      抗肿瘤活性     
Design, synthesis and study of anti-tumor activity of thiazolinone urea derivatives bearing aryloxypyridinone fragments
QI Bao-hui, YANG Ying, GONG Guo-wei, HE Huan, YUE Xu-peng, XU Xin, WANG Ya-rong
Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai 519041, China
Abstract:
Taking cabozantinib as leading compound, 13 novel small molecular c-Met inhibitors were designed and synthesized based on the obtained structure-activity relationships (SARs) of c-Met inhibitors. The structures of compounds were confirmed by 1H NMR, 13C NMR and HR-MS. In vitro anti-tumor activity was evaluated by MTT method, and the mechanism was preliminarily disclosed by real-time dynamic living cell imaging and flow cytometry analysis. The results indicated that most of compounds showed good inhibition activity against human non-small-cell carcinoma cell A549 and human colorectal cancer cell HT-29 which was superior to cabozantinb. Compounds showed excellent cytotoxity and anti-proliferative activity against HT-29, and promoted cell apoptosis.
Key words:    aryloxypyridinone    thiazolinone ureas    design    synthesis    anti-tumor activity   
收稿日期: 2018-08-20
DOI: 10.16438/j.0513-4870.2018-0760
基金项目: 国家自然科学基金资助项目(21562053);贵州省科学技术基金项目资助(黔科合J字[2014]2181号);贵州省科技合作计划项目资助(黔科合LH字[2015]7523号).
通讯作者: 祁宝辉,Tel:86-756-7623365,E-mail:bhqi@zmu.gd.cn
Email: bhqi@zmu.gd.cn
相关功能
PDF(539KB) Free
打印本文
0
作者相关文章
祁宝辉  在本刊中的所有文章
杨颖  在本刊中的所有文章
宫帼唯  在本刊中的所有文章
何欢  在本刊中的所有文章
岳续朋  在本刊中的所有文章
徐昕  在本刊中的所有文章
王雅溶  在本刊中的所有文章

参考文献:
[1] Schmeller T, Latz-Brüning B, Wink M. Biochemical activities of berberine, palmatine and sanguinarine mediating chemical defence against microorganisms and herbivores[J]. Phytochemistry, 1997, 44:257-266.
[2] Hu Z, Xu Y, Feng S, et al. Studies on the active principles of the fruits of Macleaya cordata (Willd.) R. Br.[J]. Acta Pharm Sin (药学学报), 1979, 14:535-540.
[3] Ye F, Feng F, Liu W. Alkaloids from Macleaya cordata[J]. China J Chin Mater Med (中国中药杂志), 2009, 34:1683-1686.
[4] Qin H, Wang P, Li Z, et al. The establishment of the control substance and 1H NMR nuclear magnetic resonance fingerprint of Macleaya microcarpa (Maxim.) Fedde[J]. Chin J Anal Chem (分析化学), 2004, 32:1165-1170.
[5] Oechslin SM, König GM, Oechslin-Merkel K, et al. An NMR study of four benzophenanthridine alkaloids[J]. J Nat Prod, 1991, 54:519-524.
[6] Zhou JY, Chen BZ, Tong XJ, et al. Chemical study on Chelidonium majus alkaloids[J]. Chin Tradit Herb Drugs (中草药), 1989, 20:2-4.
[7] Zuo JL, Bai L, Song XX, et al. Simultaneous determination of sanguinarine, berberine and chelerythrine in Chelidonium majus by RP-HPLC[J]. Chin J Pharm Anal (药物分析杂志), 2008, 28:903-905.
[8] Caballero-George C, Vanderheyden PML, Apers S, et al. Inhibitory activity on binding of specific ligands to the human angiotensin Ⅱ AT1 and endothelin 1 ETA receptors:bioactive benzo[c] phenanthridine alkaloids from the root of Bocconia frutescens[J]. Planta Med, 2002, 68:770-775.
[9] Dai B, Zhang MJ, Tian SJ, et al. Research progress on application and pharmacological activity of sanguinarine[J]. J Tradit Chin Vet Med (中兽医医药杂志), 2015, (4):73-75.
[10] Caballero-George C, Vanderheyden PML, Solis PN, et al. In vitro effect of sanguinarine alkaloid on binding of[3H] candesartan to the human angiotensin AT1 receptor[J]. Eur J Pharmcol, 2003, 458:257-262.
[11] Ahsan H, Reagan-Shaw S, Breur J, et al. Sanguinarine induces apoptosis of human pancreatic carcinoma AsPC-1 and BxPC-3 cells via modulations in Bcl-2 family proteins[J]. Cancer Lett, 2007, 249:198-208.
[12] Ping G, Wang Y, Shen L, et al. Highly efficient complexation of sanguinarine alkaloid by carboxylatopillar [6] arene:pKa shift, increased solubility and enhanced antibacterial activity[J]. Chem Commun, 2017, 53:7381-7384.
[13] Janovská M, Kubala M, Šimánek V, et al. Fluorescence of sanguinarine:fundamental characteristics and analysis of interconversion between various forms[J]. Anal Bioanal Chem, 2009, 395:235-240.
[14] Nakanishi T, Suzuki M, Mashiba A, et al. Synthesis of NK109, an anticancer benzo[c]phenanthridine alkaloid[J]. J Org Chem, 1998, 63:4235-4239.
[15] Maestri G, Larraufie MH, Derat Ĕ, et al. Expeditious synthesis of phenanthridines from benzylamines via dual palladium catalysis[J]. Org Lett, 2010, 12:5692-5695.
[16] Ishii H, Ishikawa T, Watanabe T, et al. Conversion of the naturally occurring amide alkaloids into O5 benzo[c]phenanthridinium alkaloids. A new synthetic sequence to antitumor benzo[c]phenanthridine alkaloids[J]. J Chem Soc, Perkin Trans I, 1984:2283-2289.
[17] Harayama T. Synthesis of benzo[c]phenanthridine alkaloids using a palladium-catalyzed aryl-aryl coupling reaction[J]. Heterocycles, 2005, 65:697-713.
[18] De S, Mishra S, Kakde BN, et al. Expeditious approach to pyrrolophenanthridones, phenanthridines, and benzo[c] phenanthridines via organocatalytic direct biaryl-coupling promoted by potassium tert-butoxide[J]. J Org Chem, 2013, 78:7823-7844.
[19] Ishii H, Ishikawa T, Ichikawa YI, et al. Studies on the chemical constituents of Rutaceous plants. LV. The development of a versatile method for the synthesis of antitumor active benzo[c] phenanthridine alkaloids. (5). A new method for quaternization of the benzo[c]phenanthridine nucleus[J]. Chem Pharm Bull, 1984, 32:2984-2994.
[20] Nakanishi T, Suzuki M, Saimoto A, et al. Structural considerations of NK109, an antitumor benzo[c]phenanthridine alkaloid[J]. J Nat Prod, 1999, 62:864-867.
[21] Guo J, Dong W, Liu W, et al. Synthesis and cytotoxicity of 3-aryl acrylic amide derivatives of the simplified saframycin-ecteinascidin skeleton prepared from L-dopa[J]. Eur J Med Chem, 2013, 62:670-676.
相关文献:
1.林菁菁, 杨亚军, 沈珑瑛, 潘显道.抗肿瘤药玫瑰树碱及其衍生物的合成和药理研究进展[J]. 药学学报, 2017,52(9): 1387-1396
2.宋彬彬, 张自阔, 朱庆枫, 何谷, 范举正.MEK小分子抑制剂的设计、合成与初步活性研究[J]. 药学学报, 2017,52(3): 416-424
3.周玉美, 崔华清, 俞晓明, 张首国, 彭涛, 王刚, 温晓雪, 孙云波, 刘曙晨, 王林.苯并咪唑和苯并噻唑类衍生物的合成及其sirtuins抑制活性评价[J]. 药学学报, 2017,52(5): 773-778
4.裴婷, 刘芳, 邓艾平.环丙沙星与组蛋白去乙酰化酶抑制剂缀合物的合成及抗肿瘤活性[J]. 药学学报, 2016,51(12): 1871-1880
5.杨家强, 曾发奎, 杨旋, 黎鹏.含氨基酸片段的膦酸酯衍生物合成与抗肿瘤作用[J]. 药学学报, 2016,51(7): 1105-1109
6.杨家强, 刘思兰, 车万莉, 张茂生, 万小强, 简宏禄, 陈永正.新型E-2,3-二芳基丙烯酰氧基膦酸酯衍生物的设计、合成与抗肿瘤活性[J]. 药学学报, 2015,50(4): 464-468
7.王永成, 李玉山, 杨瀚泽, 李燕, 陈晓光, 冯志强.新型姜黄素类似物的合成及初步抗肿瘤活性研究[J]. 药学学报, 2014,49(7): 1022-1028
8.朱齐凤, 龚永祥, 钟金清, 刘礼飞, 李旭飞, 赵旭阳.新型4-取代-3-硝基苯甲酰胺类似物的设计、合成及活性研究[J]. 药学学报, 2014,49(8): 1143-1149
9.刘文虎, 常晋霞, 刘 毅, 罗杰伟, 张建武.新型含芳基哌嗪的苯并噻唑衍生物的设计、合成及活性研究[J]. 药学学报, 2013,48(8): 1259-1265
10.王学军, 刘建利, 王江凯.丹皮酚衍生物的合成及其抗肿瘤细胞增殖研究[J]. 药学学报, 2012,47(1): 72-76
11.陈红莉 冯慧瑾 李援朝.补骨脂酚的体外抗肿瘤活性及其关键中间体的合成研究[J]. 药学学报, 2010,45(4): 467-470
12.程永浩 郭彦伸 韩海珠 王楠 张国宏 郭宗儒 吴松.新型组蛋白去乙酰化酶抑制剂的合成及抗肿瘤活性研究[J]. 药学学报, 2010,45(6): 735-741
13.冯 娟 解 鹏 翁志洁 闫征 王楠 李建其 .N-取代苯甲酰胺类衍生物的合成与抗肿瘤活性[J]. 药学学报, 2009,44(6): 603-608
14.史丽鸿 金东哲 周伟澄 王娟 陈秀华.3'-甲基呋喃核苷衍生物的设计合成与抗肿瘤活性[J]. 药学学报, 2009,44(7): 747-753
15.冯 娟 李建其.N-(氨基吡啶)苯甲酰胺类衍生物的合成与抗肿瘤活性[J]. 药学学报, 2009,44(12): 1376-1382
16.周双生;张群英;秦凯;鲁传华;谢复新.三氮杂十环及其铂(II)配合物的合成以及抗肿瘤活性[J]. 药学学报, 2008,43(5): 490-494
17.贾红;郭彦伸;葛轶昱;文辉;杨静;杨秀颖;杜冠华;杨光中.基于酶结构的新型基质金属蛋白酶抑制剂设计、合成与活性评价[J]. 药学学报, 2007,42(12): 1271-1281
18.王宾;潘显道;刘红岩;杨晶;吕昭云;赵敬华.硫代秋水仙碱衍生物的合成和抗肿瘤活性[J]. 药学学报, 2006,41(11): 1057-1063
19.李弟灶;王存英;潘显道;刘红岩;付招娣;吴松.六环喜树碱衍生物的合成与抗肿瘤活性研究[J]. 药学学报, 2005,40(3): 241-247
20.赵翠花;陈奕;丁健;段文虎.喹喔啉衍生物的设计合成及抗肿瘤活性研究[J]. 药学学报, 2005,40(9): 814-819
21.潘显道;刘红岩;孙飘扬;朱承根;杨晶;袁开红;韩锐.20-位酯化喜树碱衍生物的合成和抗肿瘤活性[J]. 药学学报, 2004,39(8): 591-597
22.阮继武;黄金凤;符立梧;黄志纾;马林;古练权.多芳基取代蝶啶类化合物的合成及其抗肿瘤活性多芳基取代蝶啶类化合物的合成及其抗肿瘤活性[J]. 药学学报, 2004,39(5): 342-347
23.杨玉社;嵇汝运;陈凯先;丁健.左旋氧氟沙星类似物的合成及其抗菌抗肿瘤活性研究[J]. 药学学报, 1999,34(2): 119-124
24.许天林;华维一;倪沛洲;蒋巡天;毕梦宇;裴咏梅;严兵.N-取代-O-对甲脒苯胺基羰甲基-L-酪氨酸甲酯类化合物的合成及抗血小板聚集活性[J]. 药学学报, 1999,34(6): 428-433