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
-
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.
-
Keywords:
- pefloxacin /
- fluoroquinolone-3-carbaldehyde /
- rhodanine /
- unsaturated ketone /
- bioisostere /
- antitumor activity
-
-
[1] Fief CA,Hoang KG,Phipps SD,et al.Examining the impact of antimicrobial fluoroquinolones on human DNA topoisomerase IIα and IIβ[J].ACS Omega,2019,4(2):4049-4055. [2] Hu W,Huang XS,Wu JF,et al.Discovery of novel topoisomerase II inhibitors by medicinal chemistry approaches[J].J Med Chem,2018,61(20):8947-8980. [3] Bisacchi GS,Hale MR.A “double-edged” scaffold:antitumor power within the antibacterial quinolone[J].Curr Med Chem,2016,23(6):520-577. [4] Jiang YL,Li K,Huang WL,et al.Synthesis and antitumor activity of 3-(benzylidene thiazolotriazolone)fluoroquinolones[J].J China Pharm Univ(中国药科大学学报),2018,49(6):671-675. [5] Yang T,Wang XM,Wang R,et al.Synthesis and antitumor activity of pefloxacin C-3(rhodanine unsaturated ketone)amide derivatives[J].J China Pharm Univ(中国药科大学学报),2017,48(5):543-547. [6] Jackson PA, Widen JC, Harki DA, et al. Covalent modifiers:a chemical perspective on the reactivity of α,β-unsaturated carbonyls with thiols via hetero-Michael addition reactions[J].J Med Chem,2017,60(3):839-885. [7] Xiang Y,Chen C,Wang WM,et al.Rhodanine as a potent scaffold for the development of broad-spectrum metallo-β-lactamase inhibitors[J].ACS Med Chem Lett,2018,9(4):359-364. [8] Xie YS,Gao LZ,Yan Q,et al.Synthesis and antitumor activity of fluoroquinolone C-3 isosteres(VIII):s-triazole sulfide-one thiosemicarbazone derivatives from pefloxacin[J].J China Pharm Univ(中国药科大学学报),2015,46(4):416-420. [9] Brown FC,Bradsher CK,Bond SM,et al.Rhodanine derivatives[J].J Am Chem Soc,1951,73(5):2357-2359. [10] Kondo H,Sakamoto F,Kawakami K,et al.Studies on prodrugs.7.Synthesis and antimicrobial activity of 3-formylquinolone derivatives[J].J Med Chem,1988,31(1):221-225. [11] McFadyen JS,Stevens TS.A new method for the conversion of acids into aldehydes[J].J Chem Soc,1936,58:584-587. [12] Chen LH,Xie L,Xie JX.Total synthesis of an analog of schizandrin[J].Acta Pharm Sin(药学学报),1991,26(1):20-24. -
期刊类型引用(2)
1. 冯惠，王晓辉，王菊，冯长君. 培氟沙星均三唑硫醚类化合物抗增殖活性的3D-QSAR研究与分子设计. 云南大学学报(自然科学版). 2021(01): 142-146 . 
百度学术
2. 唐自强，刘长宁，冯长君. 培氟沙星均三唑硫醚衍生物抗肝癌活性的CoMFA模型与分子设计. 化学通报. 2020(10): 935-939 . 百度学术
其他类型引用(0)
计量
- 文章访问数: 451
- HTML全文浏览量: 0
- PDF下载量: 711
- 被引次数: 2
下载:
