减毒5-氟尿嘧啶乳糖苷衍生物的合成及抗口腔鳞状细胞癌活性的实验研究

doi:10.7518/hxkq.2022.01.005

华西口腔医学杂志 ›› 2022, Vol. 40 ›› Issue (1): 32-38.doi: 10.7518/hxkq.2022.01.005

减毒5-氟尿嘧啶乳糖苷衍生物的合成及抗口腔鳞状细胞癌活性的实验研究

张羽婷¹(), 刘江¹, 赵行¹, 何杨², 陈谦明¹()

^1.口腔疾病研究国家重点实验室国家口腔疾病临床医学研究中心中国医学科学院口腔黏膜癌变与防治创新单元四川大学华西口腔医院口腔黏膜病科，成都 610041
^2.呼吸健康研究所靶向示踪研究室，疾病分子网络前沿科学中心，四川大学华西医院呼吸与重症医学科，成都 610041

收稿日期:2021-02-05 修回日期:2021-12-03 出版日期:2022-02-01 发布日期:2022-02-07
通讯作者: 陈谦明 E-mail:1501379093@qq.com;qmchen@scu.edu.cn
作者简介:张羽婷，硕士，E-mail：1501379093@qq.com
基金资助:
四川大学华西医院新型冠状病毒肺炎疫情科技攻关项目(HX2019nCoV056);中国博士后科学基金面上项目(2019M660240);四川省中央引导地方科技发展专项(2018SZYD0001);成都市科技成果转化引导计划项目(2017-CY02-00025-GX)

Synthesis of 5-fluorouracil-lactoside derivatives and experimental study on their anti-oral squamous cell carcinoma activity

Zhang Yuting¹(), Liu Jiang¹, Zhao Hang¹, He Yang², Chen Qianming¹()

^1.State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management & Dept. of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
^2.Targeted Tracer Research and Development Laboratory, Frontiers Science Center for Disease-related Molecular Network, Dept. of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China

Received:2021-02-05 Revised:2021-12-03 Online:2022-02-01 Published:2022-02-07
Contact: Chen Qianming E-mail:1501379093@qq.com;qmchen@scu.edu.cn
Supported by:
The Fast-track Grants of SARS-CoV-2 Research from West China Hospital, Sichuan University(HX2019nCoV056);General Program of China Postdoctoral Science Foundation(2019M660240);The Central Government Guides Local Science and Technology Development Fund of Sichuan Province(2018SZYD0001);National Fund for Technology Transfer Commercialization of Chengdu(2017-CY02-00025-GX);Correspondence: Chen Qianming, E-mail: qmchen@scu.edu.cn

摘要/Abstract

摘要： 目的

为降低5-氟尿嘧啶（5-FU）毒性，设计并合成了5-FU乳糖苷衍生物，并初步探究其抗肿瘤活性。

方法

采用Vorbrüggen法合成5-FU乳糖苷衍生物，通过高分辨质谱（HRMS）、核磁共振氢谱（¹HNMR）、核磁共振碳谱（¹³CNMR）、异核多量子相干谱（HMQC）及异核多键相关谱（HMBC）表征其结构，并用细胞计数试剂盒8（CCK-8）研究其体外毒性及抗肿瘤活性。

结果

用简单高效的方法合成了目标化合物Ⅰa、Ⅰb，并通过HRMS、¹HNMR、¹³CNMR、HMQC及HMBC证实了Ⅰa、Ⅰb分别为N-1位及N-3位乳糖基取代的5-FU核苷衍生物；经CCK-8法验证较高浓度（0.7 μmol·mL^-1）Ⅰa、Ⅰb处理24 h对正常口腔角质形成细胞NOK生长的抑制率分别为30.28%及50.68%，均较5-FU的抑制作用弱（68.22%，P<0.05），其中Ⅰb对2种口腔鳞状细胞癌细胞的生长均有较显著的抑制作用，0.7 μmol·mL^-1浓度下处理Cal-27细胞及UM SCC-47细胞24 h后抑制率分别为81.20%、80.19%。

结论

目标化合物Ⅰa、Ⅰb较5-FU具有较低毒性，且Ⅰb较Ⅰa具有更明显的抗口腔鳞状细胞癌细胞增殖活性。

关键词: 5-氟尿嘧啶, 乳糖苷衍生物, 减毒, 抗肿瘤, 口腔鳞状细胞癌

Abstract: Objective

To reduce the toxicity of 5-fluorouracil (5-FU), design and synthesize 5-FU-lactoside derivatives, and preliminarily study their antitumor activities.

Methods

Target compounds were prepared with Vorbrüggenglycation procedures, the structures were characterized through high resolution mass spectrometry (HRMS), ¹H nuclear magnetic resonance (¹HNMR), carbon-13 nuclear magnetic resonance (¹³CNMR), heteronuclear multiple quantum correlation (HMQC), and heteronuclear multiple bond correlation (HMBC). A cell counting kit (CCK)-8 test was performed to examine their in vitro toxicity and antitumor activity. Experimental data were tested by χ², and statistically significant differences were denoted by P<0.05.

Results

The target compounds were synthesized through a simple and efficient method. ¹HNMR, ¹³CNMR, HMQC, HMBC, and HRMS confirmed that Ⅰa and Ⅰb were 5-FU nucleoside derivatives substituted with lactoside groups at N-1 and N-3, respectively. The CCK-8 test verified that high concentrations (0.7 μmol·mL^-1) of Ⅰa and Ⅰb inhibited the growth of normal oral keratinocytes (NOK) by 30.28% and 50.68% after 24 h of treatment. Both values were lower than the inhibitory effect of 5-FU (68.22%; P<0.05). Ⅰb had a significant inhibitory effect on the growth of two oral squamous cell carcinoma cell lines. The inhibition rates of Cal-27 cells and UM SCC-47 cells treated with 0.7 μmol·mL^-1 for 24 h were 81.20% and 80.19%, respectively.

Conclusion

Ⅰa and Ⅰb are less toxic than 5-FU. The antitumor activity of Ⅰb against oral squamous cell carcinoma cells is more obvious than that of Ⅰa.

Key words: 5-fluorouracil, lactoside derivatives, reduced toxicity, antitumor, oral squamous cell carcinoma

中图分类号:

R 914

张羽婷, 刘江, 赵行, 何杨, 陈谦明. 减毒5-氟尿嘧啶乳糖苷衍生物的合成及抗口腔鳞状细胞癌活性的实验研究[J]. 华西口腔医学杂志, 2022, 40(1): 32-38.

Zhang Yuting, Liu Jiang, Zhao Hang, He Yang, Chen Qianming. Synthesis of 5-fluorouracil-lactoside derivatives and experimental study on their anti-oral squamous cell carcinoma activity[J]. West China Journal of Stomatology, 2022, 40(1): 32-38.

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处理时间	化合物	TC₅₀/（μmol·mL^-1）	IC₅₀/ （μmol·mL^-1）		SI
处理时间	化合物	NOK	Cal-27	UM SCC-47	Cal-27	UM SCC-47
24 h	Ⅰa	1.188	0.842	0.618	1.41	1.92
	Ⅰb	0.701	0.197	0.419	3.56	1.67
	5-FU	0.558	0.004	0.318	139.50	1.75
72 h	Ⅰa	6.879	0.756	0.590	9.10	11.66
	Ⅰb	0.245	0.150	0.248	1.63	0.99
	5-FU	0.026	0.005	0.005	5.20	5.20

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减毒5-氟尿嘧啶乳糖苷衍生物的合成及抗口腔鳞状细胞癌活性的实验研究

Synthesis of 5-fluorouracil-lactoside derivatives and experimental study on their anti-oral squamous cell carcinoma activity

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