李书平,姜亚玲,王蕊,胡国强
LI Shuping,JIANG Yaling,WANG Rui,HU Guoqiang

• 1:郑州工业应用技术学院药学应用技术研究所
• 2:河南大学公共卫生健康研究所
• 3:河南大学化学生物研究所

摘要(Abstract)：

目的基于氟喹诺酮的作用机制和结构特征设计抗肿瘤氟喹诺酮化合物。方法 1,2,4-三唑杂环作为恩诺沙星C-3上羧基的电子等排体,硫基乙酰腙作为功能修饰侧链,设计合成了新的1,2,4-三唑硫基乙酰腙类氟喹诺酮C-3衍生物(7a-7l),其结构经元素分析和光谱数据确证,用M TT[3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide]方法评价了体外对SMMC-7721、L1210和HL60共3种癌细胞的抗增殖活性。结果合成了12个新目标物,对3种癌细胞抗肿瘤活性强于母体恩诺沙星。构效关系表明,2-羟基苯环基或吸电子基取代苯基类化合物的活性强于其他取代基的化合物,其中对SMMC-7721细胞的活性与对照阿霉素相当。结论硫基乙酰腙功能基修饰的1,2,4-三唑杂环替代氟喹诺酮C-3上羧基有利于提高抗肿瘤活性。
Objective To explore an effective strategy for mechanism and structure-based antitumor fluoroqunolone design. Methods An azole heterocyclic ring,s-triazole,was used as a bioisostere of the C-3 carboxylic group and further modified with a functionalized side-chain of thioacetohydrazone to design the new(7 a-7 l) compound. MTT assay was used to evaluate the antitumor activity of SMMC-7721,L1210 and HL60 cells in vitro. Results Twelve novel title compounds 7 a-7 l were synthesized from enrofloxacin 1 and characterized by elemental analysis and spectral data. The title compounds exhibited more significantly anti-proliferative activity against three tested tumor cell lines than the parent 1. Meanwhile,structure-activity relationship showed that compounds bearing an electron-withdrawing group at benzene ring showed more potency than other compounds. In particular,benzene sulfonamide compound 7 l(IC50= 1. 2 mol·L~(-1))displayed a comparable antitumor activity against SMMC-7721 cells to the control doxorubicin(IC50=2. 5 mol·L~(-1)). Conclusions It suggests that a triazole ring modified with functionalized side-chain as a bioisosteric replacement of the C-3 carboxylic group is favorable to the improvement of antitumor activity.

关键词(KeyWords)： 氟喹诺酮;恩诺沙星;1,2,4-三唑;生物电子等排;酰腙;抗肿瘤活性
fluoroquilone;enrofloxacin;1,2,4-triazole;bioisostere;acylhydrazone;antitumor activity

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金资助项目(20872028,21072045)

作者(Author): 李书平,姜亚玲,王蕊,胡国强
LI Shuping,JIANG Yaling,WANG Rui,HU Guoqiang

DOI: 10.14066/j.cnki.cn21-1349/r.2018.03.002

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