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
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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Keywords:
- pefloxacin /
- fluoroquinolone-3-carbaldehyde /
- rhodanine /
- unsaturated ketone /
- bioisostere /
- antitumor activity
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