药学学报, 2015, 50(5): 569-573
引用本文:
李涛, 高留州, 谢玉锁, 冯焱飞, 闫强, 吴书敏, 倪礼礼, 赵辉, 黄文龙, 胡国强. 氟喹诺酮C-3稠杂环α,β-不饱和酮衍生物的合成与抗增殖活性[J]. 药学学报, 2015, 50(5): 569-573.
LI Tao, GAO Liu-zhou, XIE Yu-suo, FENG Yan-fei, YAN Qiang, WU Shu-min, NI Li-li, ZHAO Hui, HUANG Wen-long, HU Guo-qiang. Synthesis and anti-proliferative activity of fluoroquinolone C-3 fused heterocyclic α, β-unsaturated ketones derived from ciprofloxacin[J]. Acta Pharmaceutica Sinica, 2015, 50(5): 569-573.

氟喹诺酮C-3稠杂环α,β-不饱和酮衍生物的合成与抗增殖活性
李涛1, 高留州1, 谢玉锁1, 冯焱飞1, 闫强1, 吴书敏1, 倪礼礼1, 赵辉1*, 黄文龙2, 胡国强1*
1. 河南大学化学生物学研究所, 河南 开封 475001;
2. 中国药科大学新药研究中心, 江苏 南京 210009
摘要:
为发现新的抗肿瘤氟喹诺酮先导化合物, 用噻唑并[3,2-b][1,2,4]三唑酮稠杂环作为环丙沙星C-3羧基的等排体, 进一步与芳香醛发生Claisen缩合构建成C-3稠杂环α, β-不饱和酮类目标化合物6a6r, 其结构经元素分析、1H NMR、MS确证。采用MTT法评价了目标化合物对人肝癌Hep-3B细胞、人胰腺癌Capan-1细胞及人白血病HL60细胞的体外增值抑制活性。结果表明, 18个目标化合物对3种实验癌细胞的抗增殖活性均显著高于母体环丙沙星1的活性, 其中对Capan-1细胞的活性最强, 尤其是苯环带有吸电子羧基 (6k6m) 和磺酰胺基 (6q6r) 化合物的活性相当于或优于对照抗肿瘤药物阿霉素的活性。以上的结果表明, 氟喹诺酮C-3羧基用稠杂环不饱和酮取代有利于提高其抗肿瘤活性。
关键词:    氟喹诺酮      噻唑并三唑酮      不饱和酮      抗增殖活性     
Synthesis and anti-proliferative activity of fluoroquinolone C-3 fused heterocyclic α, β-unsaturated ketones derived from ciprofloxacin
LI Tao1, GAO Liu-zhou1, XIE Yu-suo1, FENG Yan-fei1, YAN Qiang1, WU Shu-min1, NI Li-li1, ZHAO Hui1*, HUANG Wen-long2, HU Guo-qiang1*
1. Institute of Chemistry and Biology, Henan University, Kaifeng 475001, China;
2. Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China
Abstract:
To discover novel antitumor fluoroquinolone lead compounds from a rational modification for antibacterial fluoroquinolones, a fused heterocyclic ketone corresponding to thiazolo[2,3-b][1,2,4]triazolone used as a bioisosteric replacement of the C-3 carboxylic acid group of ciprofloxacin 1, and further modification by a Claisen condensation reaction with substituted benzaldehydes formed novel fluoroquinolone C-3 fuse heterocyclic α, β-unsaturated ketones as the title compounds (6a-6r), separately. The structures of eighteen title compounds were characterized by elemental analysis, 1H NMR and MS, and the in votro anti-proliferative activity against human hepatoma Hep-3B cells, pancreatic Capan-1 cells and leukemia HL60 cells was evaluated by a MTT assay. The preliminary results showed that the title compounds not only had more significant anti-proliferative activity against three tested cancer cell lines than that of the parent ciprofloxacin 1, but also exhibited the highest activity against Capan-1 cells. In particular, compounds carrying an electron-withdrawing carboxyl (6k, 6m) or sulfonamide substituent (6q, 6r) attached to benzene ring were comparable to or better than constractive drug doxorubicin against Capan-1 cells. As such, it suggests that it is favorable for a fused heterocyclic α, β-unsaturated ketone scaffold instead of the C-3 carboxylic acid group to improve the antitumor activity of fluoroquinolones.
Key words:    fluoroquinolone    thiazolotriazolone    unsaturated ketone    anti-proliferative activity   
收稿日期: 2014-10-31
基金项目: 国家自然科学基金资助项目 (20872028, 21072045); 河南大学科研基金资助项目.
通讯作者: 赵辉, 胡国强
Email: hgqxy@sina.com.cn
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参考文献:
[1] Guo ZR. Modification of natural products for drug discovery [J]. Acta Pharm Sin (药学学报), 2012, 47: 209-218.
[2] Guo ZR. Strategy of molecular drug design: dual-target drug design [J]. Acta Pharm Sin (药学学报), 2009, 44: 144-157.
[3] Takiff H, Guerrero E. Current prospects for the fluoroqui­nolones as first-line tuberculosis therapy [J]. Antimicrob Agents Chemother, 2011, 55: 5421-5429.
[4] Hu GQ, Hou LL, Wang GQ, et al. Part IV: Design, synthesis and antitumor activity of fluoroquinolone C-3 heterocycles: bis- oxadiazole methylsulfide derivatives derived from ciprofloxacin [J]. Acta Pharm Sin (药学学报), 2012, 47: 1017-1022.
[5] Xie SQ, Chen YS, Wang GQ, et al. Part IV. Synthesis and antitumor evaluation of s-triazolothiadiazines and pyrazolo s-triazoles derived from ciproxacin [J]. Acta Pharm Sin (药学学报), 2012, 47: 66-71.
[6] Cao X, Sun Z, Cao Y, et al. Design, synthesis, and structure- activity relationship studies of novel fused heterocycles-linked triazoles with good activity and water solubility [J]. J Med Chem, 2014, 57: 3687-36706.
[7] Karpaviciene I, Cikotiene I, Padrón JM. Synthesis and antiproliferative activity of α-branched α, β-unsaturated ketones [J]. Eur J Med Chem, 2014, 70: 568-578.
[8] Bukhari SN, Jasamai M, Jantan I. Synthesis and biological evaluation of chalcone derivatives (mini review) [J]. Mini Rev Med Chem, 2012, 12: 1394-1403.
[9] Sun L, Liang C, Shirazian Z, et al. Discovery of 5-[5-fluoro- 2-oxo-1, 2-dihydroindol-(3Z)-ylidenemethyl]-2, 4-dimethyl-1H- pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase [J]. J Med Chem, 2003, 46: 1116-1119.
[10] Wang Y, Long YQ. Advances in small-molecule inhibitors of protein tyrosine kinases [J]. Chin J Org Chem (有机化学), 2011, 31: 1595-1606.