培氟沙星C-3甲叉基绕丹宁衍生物的合成及其抗肿瘤活性
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国家自然科学基金资助项目(No.20872028,No.21072045);河南省科技发展计划资助项目(No.162102310392);河南省教育厅科学技术研究重点资助项目(No.15A350004)和郑州工业应用技术学院自然科学研究资助项目(No.2018YB022)


Synthesis and antitumor activity of pefloxacin C-3 methylene rhodanine devatives
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    摘要:

    为进一步寻找抗肿瘤氟喹诺酮分子的构建策略,用α,β-不饱和酮为抗菌氟喹诺酮C-3羧基的生物电子排体、绕丹宁环为其稠合功能修饰基进而构建了氟喹诺酮C-3甲叉基绕丹宁类1-乙基-6-氟-7-(4-甲基哌嗪-1-基)-3-[3-取代-2-硫代噻唑烷-4-酮-5-叉甲基]-喹啉-4(1H)-酮(6a~6l)目标化合物,其结构经元素分析和光谱数据确证。初步的体外抗细胞增殖活性筛选结果表明,12个新目标化合物对A549、Hep-3B、HL60 3种肿瘤细胞的活性显著高于母体培氟沙星(1),尤其卤代苯基绕丹宁化合物的活性强于其他取代基,对人非小细胞肺肿瘤细胞A549的活性与对照阿霉素相当,且对正常细胞Vero表现出较低细胞毒作用,显示出较好的选择性。为此,甲叉基绕丹宁替代C-3羧基的衍生物有利于提高氟喹诺酮的抗肿瘤活性。

    Abstract:

    To further explore an efficient strategy for the construction of antitumor fluoroquinolone molecules from antibacterial fluoroquinolone drugs, twelve new title compounds, 1-ethyl-6-fluoro-7-(4-methyl-piperazin-1-yl)-3-(3-substituted-rhodanin-5-ylidene)methyl-quinolon-4(1H)-ones(6a-6l), was designed and synthesized with α, β-unsaturated ketone scaffold and a rhodanine ring as an isostere and fused modified group, respectively, from pefloxacin(1), and their structures were characterized by elemental analysis and spectral data. The in vitro anti-cell proliferative activity of the title compounds against the tested A549, Hep-3B and HL60 cancer cells exhibited more significant potency than parent 1. In particular, halogenated phenyl title compounds(6d, 6e, 6f)displayed a comparable activity to comparison doxorubicin against A549 cells and low cytotoxicity against normal Vero cells. Thus, a methylene rhodanine scaffold as a bioisostere of the C-3 carboxylic acid group have shown to be beneficial to improving the antitumor activity.

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张会丽,卢光莉,黄文龙,胡国强.培氟沙星C-3甲叉基绕丹宁衍生物的合成及其抗肿瘤活性[J].中国药科大学学报,2019,50(6):672-677.
Cite:ZHANG Huili, LU Guangli, HUANG Wenlong, HU Guoqiang. Synthesis and antitumor activity of pefloxacin C-3 methylene rhodanine devatives[J]. J China Pharm Univ,2019,50(6):672-677.

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  • 在线发布日期: 2019-12-31
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