目的 为发现抗菌氟喹诺酮向抗肿瘤活性转化的有效修饰策略。方法 以均三唑为氧氟沙星C-3羧基的等排体、通过缩环合反应设计了C-3噻二唑并均三唑稠杂环目标化合物(5a~5l,6a~6l)。用元素分析和光谱数据确证化合物的结构,用MTT方法评价了目标化合物对体外培养的SMMC-7721、Capan-1和HL60 3种癌细胞株的抗增值活性。结果 合成了12个新型结构的C-3稠杂环目标化合物,体外抗肿瘤活性强于母体1和相应中间体硫醚酮5的活性,但弱于硫醚酮缩氨基硫脲化合物6的活性。结论 C-3稠杂环等排体的结构修饰值得进一步研究。
Abstract
OBJECTIVE To discover an efficient strategy for conversion of the antibacterial activity of fluoroquinolone drugs to antitumor activity. METHODS Novel title fused heterocyclic C-3 thiazolo[3,2-b][1,2,4]triazole derivatives(5,6) were designed by using a s-triazole ring as the bioisostere and modifying it by a fused condensation-cyclization reaction. The structures were validated by elemental analysis and spectral data, and the in vitro antitumor activity of the title compounds against three tested tumor cell lines was evaluated by MTT assay. RESULTS Twelve title compounds were synthesized from ofloxacin and exhibited more significant antiproliferative activity than both of parent ofloxacin 1 and the corresponding intermediate sulfide ketones 5, but displayed a slightly weaker activity than the corresponding sulfide ketone thiosemi-carbazones 6. CONCLUSION An efficient structure modification strategy for the fused heterocyclic core of thiazolotriazole used as the C-3 bioisostere warrants further development.
关键词
氟喹诺酮 /
氧氟沙星 /
稠杂环 /
噻唑并均三唑 /
等排体 /
抗肿瘤活性
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Key words
fluoroquinolone /
ofloxacin /
fused heterocycle /
thiazolotriazole /
bioisostere /
antitumor activity
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中图分类号：
R914
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参考文献
[1] ALDREKd K J, SCHWANZ H A, LI G, et al. Activity of quinolone CP-115,955 against bacterial and human type II topoisomerases is mediated by different interactions [J]. Biochemistry, 2015, 54(5): 1278-1286.
[2] ABDEL-AZIZ M, ARK S E, ABUO-RAHMA G D, et al. Novel N-4-piperazinyl-ciprofloxacin-chalcone hybrids: Synthesis, physicochemical properties, anticancer and topoisomerase I and II inhibitory activity [J]. Eur J Med Chem, 2013, 69: 427-438(doi:10.1016/j.ejmech.2013.08.040).
[3] LIU Y Q, LI W Q, MORRIS-NATSCHKE S L, et al. Perspectives on biologically active camptothecin derivatives [J]. Med Res Rev, 2015(doi: 10.1002/med.21342).
[4] HU G Q, CHEN Y S, WANG G Q, et al. Synthesis of fluoroquinolone C-3 heterocycles, bis-oxadiazole methylsulfides and methiodides, and their antitumor activity [J]. Chin Pharm J(中国药学杂志), 2012, 47(1): 72-76.
[5] HOU L L, YIN J, WANG W, et al. Synthesis and antitumor activity of fluoroquinolone C-3 heterocycles-oxadiazole derivatives(II)[J]. Chin Pharm J(中国药学杂志), 2013, 48(14): 1194-1196.
[6] XU Q J, HOU L L, WU Z F, et al. Synthesis and antitumor evaluation of fluoroquinolon C3 S-triazole oxadiazole methylsulfide derivatives of ofloxacin [J]. Chin Pharm J(中国药学杂志), 2014, 49(7):609-612.
[7] HUSSEIN M A, SHAKER R M, AMEEN M A, et al. Synthesis, anti-inflammatory, analgesic, and antibacterial activities of some triazole, triazolothiadiazole, and triazolothiadiazine derivatives[J]. Arch Pharm Res, 2011, 34(8):1239-1250.
[8] PORTER D W, BRADLEY M, BROWN Z, et al. The discovery of potent, orally bioavailable pyrazolo and triazolopyrimidine CXCR2 receptor antagonists [J]. Bioorg Med Chem Lett, 2014, 24(1): 72-76.
[9] GAO L Z, LI T,XIE Y S, et al. Synthesis and antitumor activity of fluoroquinolon-3-yl-s-triazole sulfanylacetylhydrazones and S-triazole hydrazone derivatives(V) [J]. Chin Pharm J (中国药学杂志), 2015,50(6): 545-549.
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脚注
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基金
国家自然科学基金资助项目(20872028, 21072045);河南省高等学校重点科研资助项目(15A350004)
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